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Phillips PCA, de Sousa Loreto Aresta Branco M, Cliff CL, Ward JK, Squires PE, Hills CE. Targeting senescence to prevent diabetic kidney disease: Exploring molecular mechanisms and potential therapeutic targets for disease management. Diabet Med 2025; 42:e15408. [PMID: 38995865 PMCID: PMC11733669 DOI: 10.1111/dme.15408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 06/27/2024] [Accepted: 06/28/2024] [Indexed: 07/14/2024]
Abstract
BACKGROUND/AIMS As a microvascular complication, diabetic kidney disease is the leading cause of chronic kidney disease and end-stage renal disease worldwide. While the underlying pathophysiology driving transition of diabetic kidney disease to renal failure is yet to be fully understood, recent studies suggest that cellular senescence is central in disease development and progression. Consequently, understanding the molecular mechanisms which initiate and drive senescence in response to the diabetic milieu is crucial in developing targeted therapies that halt progression of renal disease. METHODS To understand the mechanistic pathways underpinning cellular senescence in the context of diabetic kidney disease, we reviewed the literature using PubMed for English language articles that contained key words related to senescence, inflammation, fibrosis, senescence-associated secretory phenotype (SASP), autophagy, and diabetes. RESULTS Aberrant accumulation of metabolically active senescent cells is a notable event in the progression of diabetic kidney disease. Through autocrine- and paracrine-mediated mechanisms, resident senescent cells potentiate inflammation and fibrosis through increased expression and secretion of pro-inflammatory cytokines, chemoattractants, recruitment of immune cells, myofibroblast activation, and extracellular matrix remodelling. Compounds that eliminate senescent cells and/or target the SASP - including senolytic and senomorphics drugs - demonstrate promising results in reducing the senescent cell burden and associated pro-inflammatory effect. CONCLUSIONS Here we evidence the link between senescence and diabetic kidney disease and highlight underlying molecular mechanisms and potential therapeutic targets that could be exploited to delay disease progression and improve outcomes for individuals with the disease. Trials are now required to translate their therapeutic potential to a clinical setting.
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Affiliation(s)
| | | | | | - Joanna Kate Ward
- Joseph Banks Laboratories, College of Health and ScienceLincolnUK
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Götz L, Rueckschloss U, Reimer A, Bömmel H, Beilhack A, Ergün S, Kleefeldt F. Vascular inflammaging: Endothelial CEACAM1 expression is upregulated by TNF-α via independent activation of NF-κB and β-catenin signaling. Aging Cell 2025; 24:e14384. [PMID: 39434463 PMCID: PMC11822634 DOI: 10.1111/acel.14384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 09/01/2024] [Accepted: 09/25/2024] [Indexed: 10/23/2024] Open
Abstract
Chronic inflammation with progressive age, called inflammaging, contributes to the pathogenesis of cardiovascular diseases. Previously, we have shown increased vascular expression of the Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) in aged mice and humans, presumably via mutual upregulation with the pro-inflammatory cytokine TNF-α. CEACAM1 is critical for aging-associated vascular alterations like endothelial dysfunction, fibrosis, oxidative stress, and sustained inflammation and can be regarded as a main contributor to vascular inflammaging. This study was conducted to elucidate the mechanisms underlying endothelial CEACAM1 upregulation by TNF-α in detail. Using wildtype (WT) and TNF-α knockout (Tnf-/-) mice, we confirmed that the aging-related upregulation of endothelial CEACAM1 critically depends on TNF-α. The underlying mechanisms were analyzed in an endothelial cell culture model. TNF-α time-dependently upregulated CEACAM1 in vitro. In pharmacological experiments, we identified an early NF-κB- and a delayed β-catenin-mediated response. Involvement of β-catenin was further substantiated by siRNA-mediated knockdown of the β-catenin-targeted transcription factor TCF4. Both signaling pathways acted independent from each other. Elucidating the delayed response, co-immunoprecipitation analysis revealed release of β-catenin from adherens junctions by TNF-α. Finally, TNF-α activated Akt kinase by increasing its Ser473 phosphorylation. Consequently, Akt kinase facilitated β-catenin signaling by inhibiting its degradation via phosphorylation of GSK3β at Ser9 and by increased phosphorylation of β-catenin at Ser552 that augments its transcriptional activity. Taken together, our study provides novel mechanistic insights into the aging-related, inflammation-mediated endothelial upregulation of CEACAM1. Beyond the pathogenesis of cardiovascular diseases, these findings may be significant to all fields of inflammaging.
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Affiliation(s)
- Lisa Götz
- Institute of Anatomy and Cell Biology, University of WuerzburgWuerzburgGermany
| | - Uwe Rueckschloss
- Institute of Anatomy and Cell Biology, University of WuerzburgWuerzburgGermany
| | - Andreas Reimer
- Institute of Anatomy and Cell Biology, University of WuerzburgWuerzburgGermany
| | - Heike Bömmel
- Institute of Anatomy and Cell Biology, University of WuerzburgWuerzburgGermany
| | - Andreas Beilhack
- Department of Internal Medicine IIUniversity Hospital WuerzburgWuerzburgGermany
| | - Süleyman Ergün
- Institute of Anatomy and Cell Biology, University of WuerzburgWuerzburgGermany
| | - Florian Kleefeldt
- Institute of Anatomy and Cell Biology, University of WuerzburgWuerzburgGermany
- Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell InstituteHarvard UniversityCambridgeMassachusettsUSA
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Troise D, Allegra C, Cirolla LA, Mercuri S, Infante B, Castellano G, Stallone G. Exploring Potential Complement Modulation Strategies for Ischemia-Reperfusion Injury in Kidney Transplantation. Antioxidants (Basel) 2025; 14:66. [PMID: 39857400 PMCID: PMC11761266 DOI: 10.3390/antiox14010066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2024] [Revised: 01/03/2025] [Accepted: 01/06/2025] [Indexed: 01/27/2025] Open
Abstract
The complement system plays a crucial role in regulating the inflammatory responses in kidney transplantation, potentially contributing to early decline in kidney function. Ischemia-reperfusion injury (IRI) is among the factors affecting graft outcomes and a primary contributor to delayed graft function. Complement activation, particularly the alternative pathway, participates in the pathogenesis of IRI, involving all kidney compartments. In particular, tubular epithelial cells often acquire a dysfunctional phenotype that can exacerbate complement activation and kidney damage. Currently, complement-modulating drugs are under investigation for the treatment of kidney diseases. Many of these drugs have shown potential therapeutic benefits, but no effective clinical treatments for renal IRI have been identified yet. In this review, we will explore drugs that target complement factors, complement receptors, and regulatory proteins, aiming to highlight their potential value in improving the management of renal IRI.
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Affiliation(s)
- Dario Troise
- Nephrology, Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
- Division of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, 141 52 Stockholm, Sweden
| | - Costanza Allegra
- Nephrology, Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
| | - Luciana Antonia Cirolla
- Nephrology, Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
| | - Silvia Mercuri
- Nephrology, Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
| | - Barbara Infante
- Nephrology, Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
| | - Giuseppe Castellano
- Unit of Nephrology, Dialysis and Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, 20122 Milan, Italy
| | - Giovanni Stallone
- Nephrology, Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
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4
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Canaud B, Stenvinkel P, Scheiwe R, Steppan S, Bowry S, Castellano G. The Janus-faced nature of complement in hemodialysis: interplay between complement, inflammation, and bioincompatibility unveiling a self-amplifying loop contributing to organ damage. FRONTIERS IN NEPHROLOGY 2024; 4:1455321. [PMID: 39691704 PMCID: PMC11649546 DOI: 10.3389/fneph.2024.1455321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 10/31/2024] [Indexed: 12/19/2024]
Abstract
In hemodialysis (HD), complement activation, bioincompatibility, and inflammation are intricately intertwined. In the 1970s, as HD became a routine therapy, the observation of complement pathway activation and transient leukopenia by cellulosic dialysis membranes triggered the bioincompatibility debate and its clinical relevance. Extensive deliberations have covered definitions, assessment markers, scope, and long-term clinical consequences of membrane-dependent bioincompatibility reactions. While complement pathways' interplay with coagulation and inflammation has been delineated, HD's focus has primarily been on developing more biocompatible membranes using advanced technologies. Recent advances and understanding of the current HD delivery mode (4-hour sessions, thrice weekly) suggest that factors beyond membrane characteristics play a significant role, and a more complex, multifactorial picture of bioincompatibility is emerging. Chronic activation of the complement system and persistent low-grade "uremic inflammation" in chronic kidney disease (CKD) and HD lead to premature inflammaging of the kidney, resembling aging in the general population. Cellular senescence, modulated by complement activation and the uremic milieu, contributes to chronic inflammaging. Additionally, the formation of neutrophil extracellular traps (NETs, process of NETosis) during HD and their biological activity in the interdialytic period can lead to dialysis-induced systemic stress. Thus, complement-inflammation manifestations in HD therapies extend beyond traditional membrane-related bioincompatibility consequences. Recent scientific knowledge is reshaping strategies to mitigate detrimental consequences of bioincompatibility, both technologically and in HD therapy delivery modes, to improve dialysis patient outcomes.
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Affiliation(s)
- Bernard Canaud
- School of Medicine, University of Montpellier, Montpellier, France
| | - Peter Stenvinkel
- Dept of Renal Medicine, Karolinska University Hospital, Stockholm, Sweden
| | | | | | - Sudhir Bowry
- Dialysis-at-Crossroads (D@X) Advisory, Bad Nauheim, Germany
| | - Giuseppe Castellano
- Center for Hemolytic Uremic Syndrome (HUS) Prevention, Control, and Management at the Nephrology and Dialysis Unit, Fondazione Scientific Institute for Research, Hospitalization and Healthcare (IRCCS) Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
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Rinaldi A, Cippà PE, Nemazanyy I, Anglicheau D, Pallet N. Taurine Deficiency Is a Hallmark of Injured Kidney Allografts. Transplantation 2024; 108:e218-e228. [PMID: 39167563 DOI: 10.1097/tp.0000000000004987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/21/2024]
Abstract
BACKGROUND Taurine is one of the most abundant amino acids in humans. Low taurine levels are associated with cellular senescence, mitochondrial dysfunction, DNA damage, and inflammation in mouse, all of which can be reversed by supplementation. It is unknown whether taurine metabolism is associated with kidney allograft function and survival. METHODS We performed urine metabolomic profiling of kidney transplant recipients in the early and late phases after transplantation combined with transcriptomic analysis of human kidney allografts. Single-nucleus RNA sequencing data sets of mouse kidneys after ischemia-reperfusion injury were analyzed. We analyzed the association of urinary taurine levels and taurine metabolism genes with kidney function, histology, and graft survival. RESULTS Urine taurine concentrations were significantly lower in kidney transplant recipients who experienced delayed graft function. In a mouse model of ischemia-reperfusion injury, the taurine biosynthesis gene, CSAD , but not the taurine transporter SLC6A6 , was repressed. In the late stage of transplantation, low level of taurine in urine was associated with impaired kidney function and chronic structural changes. Urine taurine level in the lowest tertile was predictive of graft loss. Expression of the taurine transporter SLC6A6 in the upper median, but not CSAD , was associated with chronic kidney injury and was predictive of graft loss. CONCLUSIONS Low urine taurine level is a marker of injury in the kidney allograft, is associated with poor kidney function, is associated with chronic histological changes, and is predictive of graft survival. The differential expression of CSAD and SLC6A6 , depending on the time after transplantation and marks of injury, highlights different mechanisms affecting taurine metabolism.
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Affiliation(s)
- Anna Rinaldi
- Division of Nephrology, Department of Medicine, Ente Ospedaliero Cantonale, Lugano, Switzerland
- Laboratories for Translational Research, Ente Ospedaliero Cantonale, Bellinzona, Switzerland
- Division of Nephrology, Department of Medicine, Ente Ospedaliero Cantonale, Lugano, Switzerland
| | - Pietro E Cippà
- Division of Nephrology, Department of Medicine, Ente Ospedaliero Cantonale, Lugano, Switzerland
- Laboratories for Translational Research, Ente Ospedaliero Cantonale, Bellinzona, Switzerland
- Division of Nephrology, Department of Medicine, Ente Ospedaliero Cantonale, Lugano, Switzerland
| | - Ivan Nemazanyy
- Platform for Metabolic Analyses, Structure Fédérative de Recherche Necker, Institut National de la Santé et de la Recherche Médicale (INSERM) US24/CNRS UMS3633, Paris, France
| | - Dany Anglicheau
- INSERM U1151, Université Paris Cité, Paris, France
- Service de Néphrologie et Transplantation, Assistance Publique Hôpitaux de Paris, Hôpital Necker, Paris, France
| | - Nicolas Pallet
- Service de Biochimie, Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France
- Université de Paris, INSERM UMRS1138, Centre de Recherche des Cordeliers, Paris, France
- Service de Néphrologie, Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France
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Almalki WH, Salman Almujri S. Oxidative stress and senescence in aging kidneys: the protective role of SIRT1. EXCLI JOURNAL 2024; 23:1030-1067. [PMID: 39391060 PMCID: PMC11464868 DOI: 10.17179/excli2024-7519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Accepted: 08/07/2024] [Indexed: 10/12/2024]
Abstract
Aging leads to a gradual decline in kidney function, making the kidneys increasingly vulnerable to various diseases. Oxidative stress, together with cellular senescence, has been established as paramount in promoting the aging process of the kidney. Oxidative stress, defined as an imbalance between ROS formation and antioxidant defense mechanisms, has been implicated in the kidney's cellular injury, inflammation, and premature senescence. Concurrently, the accumulation of SCs in the kidney also exacerbates oxidative stress via the secretion of pro-inflammatory and tissue-damaging factors as the senescence-associated secretory phenotype (SASP). Recently, SIRT1, a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, has been pivotal in combating oxidative stress and cellular senescence in the aging kidney. SIRT1 acts as a potential antioxidant molecule through myriad pathways that influence diverse transcription factors and enzymes essential in maintaining redox homeostasis. SIRT1 promotes longevity and renal health by modulating the acetylation of cell cycle and senescence pathways. This review covers the complex relationship between oxidative stress and cellular senescence in the aging kidney, emphasizing the protective role of SIRT1. See also the graphical abstract(Fig. 1).
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Affiliation(s)
- Waleed Hassan Almalki
- Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Salem Salman Almujri
- Department of Pharmacology, College of Pharmacy, King Khalid University, Abha 61421, Aseer, Saudi Arabia
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Jain A, Jung HJ, Aubee J, O’Neil JN, Muhammad LA, Khan S, Thompson K, Fluitt MB, Lee DL, Klinge CM, Khundmiri SJ. Role of NHERF1 in MicroRNA Landscape Changes in Aging Mouse Kidneys. Biomolecules 2024; 14:1048. [PMID: 39334814 PMCID: PMC11430241 DOI: 10.3390/biom14091048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 08/19/2024] [Accepted: 08/20/2024] [Indexed: 09/30/2024] Open
Abstract
MicroRNAs (miRNAs) play important roles in the regulation of cellular function and fate via post-transcriptional regulation of gene expression. Although several miRNAs are associated with physiological processes and kidney diseases, not much is known about changes in miRNAs in aging kidneys. We previously demonstrated that sodium hydrogen exchanger 1 (NHERF1) expression regulates cellular responses to cisplatin, age-dependent salt-sensitive hypertension, and sodium-phosphate cotransporter trafficking. However, the mechanisms driving these regulatory effects of NHERF1 on cellular processes are unknown. Here, we hypothesize that dysregulation of miRNA-mediated gene regulatory networks that induce fibrosis and cytokines may depend on NHERF1 expression. To address this hypothesis, we compared miRNA expression in kidneys from both male and female old (12-18-month-old) and young (4-7-month-old) wild-type (WT) and NHERF1 knockout (NHERF1-/-) mice. Our results identified that miRNAs significantly decreased in NHERF1-/- mice included miR-669m, miR-590-3p, miR-153, miR-673-3p, and miR-127. Only miR-702 significantly decreased in aged WT mice, while miR-678 decreased in both WT and NHERF1-/- old versus young mice. miR-153 was shown to downregulate transcription factors NFATc2 and NFATc3 which regulate the transcription of several cytokines. Immunohistochemistry and western blotting revealed a significant increase in nuclear NFATc2 and NFATc3 in old NHERF1-/- mice compared to old WT mice. Our data further show that expression of the cytokines IL-1β, IL-6, IL-17A, MCP1, and TNF-α significantly increased in the old NHERF1-/- mice compared to the WT mice. We conclude that loss of NHERF1 expression induces cytokine expression in the kidney through interactive regulation between miR-153 and NFATc2/NFATc3 expression.
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Affiliation(s)
- Anish Jain
- Department of Physiology, Howard University College of Medicine, Washington, DC 20059, USA; (A.J.); (J.N.O.); (L.A.M.); (S.K.); (D.L.L.)
| | - Hyun Jun Jung
- Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA;
| | - Joseph Aubee
- Department of Microbiology, Howard University College of Medicine, Washington, DC 20059, USA; (J.A.); (K.T.)
| | - Jahn N. O’Neil
- Department of Physiology, Howard University College of Medicine, Washington, DC 20059, USA; (A.J.); (J.N.O.); (L.A.M.); (S.K.); (D.L.L.)
| | - Laila A. Muhammad
- Department of Physiology, Howard University College of Medicine, Washington, DC 20059, USA; (A.J.); (J.N.O.); (L.A.M.); (S.K.); (D.L.L.)
| | - Shaza Khan
- Department of Physiology, Howard University College of Medicine, Washington, DC 20059, USA; (A.J.); (J.N.O.); (L.A.M.); (S.K.); (D.L.L.)
| | - Karl Thompson
- Department of Microbiology, Howard University College of Medicine, Washington, DC 20059, USA; (J.A.); (K.T.)
| | - Maurice B. Fluitt
- Department of Medicine, Howard University College of Medicine, Washington, DC 20059, USA;
| | - Dexter L. Lee
- Department of Physiology, Howard University College of Medicine, Washington, DC 20059, USA; (A.J.); (J.N.O.); (L.A.M.); (S.K.); (D.L.L.)
| | - Carolyn M. Klinge
- Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY 40202, USA;
| | - Syed J. Khundmiri
- Department of Physiology, Howard University College of Medicine, Washington, DC 20059, USA; (A.J.); (J.N.O.); (L.A.M.); (S.K.); (D.L.L.)
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Bleich E, Vonbrunn E, Büttner-Herold M, Amann K, Daniel C. Macrophage-Induced Pro-Fibrotic Gene Expression in Tubular Cells after Ischemia/Reperfusion Is Paralleled but Not Directly Mediated by C5a/C5aR1 Signaling. Life (Basel) 2024; 14:1031. [PMID: 39202772 PMCID: PMC11355820 DOI: 10.3390/life14081031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Revised: 08/14/2024] [Accepted: 08/15/2024] [Indexed: 09/03/2024] Open
Abstract
Ischemia/reperfusion (I/R) is inevitable during kidney transplantation and causes acute kidney injury (AKI), which affects immediate outcome and leads to chronic changes such as fibrotic remodeling of the graft. We investigated pro-fibrotic signaling after I/R, focusing on the complement component and receptor C5a/C5aR1 and macrophage/tubule crosstalk. Male Dark Agouti rats were subjected to I/R and their kidneys were harvested 10 min, 6 h, 24 h, 3 days, 5 days and 8 weeks after reperfusion. The development of renal fibrosis was assessed by the detection of Vimentin (VIM), α-smooth muscle actin (α-SMA) and collagen by immunohistochemistry and Sirius Red staining, respectively. The characterization of C5a/C5aR1 activity and C5aR1+ cells was performed by multiplex mRNA analysis, ELISA, immunofluorescence flow cytometry and in situ hybridization in animal models and cell culture analyses. In the cell culture experiments, we focused on macrophage/tubule cell crosstalk in co-culture experiments and mimicked in vivo conditions by hypoxia/reoxygenation and supplementation with C5a. Already 6-24 h after the induction of I/R in the rat model, C5a concentration in the plasma was significantly increased compared to the control. The matrix components VIM and α-SMA peaked on day 5 and declined after 8 weeks, when an increase in collagen was detected using Sirius Red. In contrast to early I/R-induced C5a activation, renal C5ar1 expression was maximal at day 5 and C5 expression increased until week 8, indicating that the renal upregulation of expression is not required for early complement activation. C5aR1 mRNA was detected in neutrophils and macrophages, but not in proximal tubular cells in the injured kidneys. The macrophage/tubular cell co-culture experiments showed that macrophages were mainly responsible for the increased expression of fibrosis-associated genes in tubule cells (ACTA2, VIM, SNAI1, TGFB1 and FGF-2), and hypoxia/reoxygenation had a partially enhancing effect. A direct pro-fibrotic effect of C5a was not observed. Increased TGF-ß levels were dependent on the differentiation of macrophages to the M2 subtype. In conclusion, the early activation of mesenchymal markers in tubular epithelial cells leads to long-term fibrotic remodeling characterized by VIM expression and driven by TGF-ß-dependent macrophage/tubular crosstalk. The chemoattractive properties of complement C5a may contribute to the recruitment of pro-fibrotic macrophages.
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Affiliation(s)
| | | | | | | | - Christoph Daniel
- Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-University (FAU) Erlangen-Nuremberg, 91054 Erlangen, Germany; (E.B.); (E.V.); (M.B.-H.); (K.A.)
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Stea ED, D'Ettorre G, Mitrotti A, Gesualdo L. The complement system in the pathogenesis and progression of kidney diseases: What doesn't kill you makes you older. Eur J Intern Med 2024; 124:22-31. [PMID: 38461065 DOI: 10.1016/j.ejim.2024.02.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 01/31/2024] [Accepted: 02/09/2024] [Indexed: 03/11/2024]
Abstract
The Complement System is an evolutionarily conserved component of immunity that plays a key role in host defense against infections and tissue homeostasis. However, the dysfunction of the Complement System can result in tissue damage and inflammation, thereby contributing to the development and progression of various renal diseases, ranging from atypical Hemolytic Uremic Syndrome to glomerulonephritis. Therapeutic interventions targeting the complement system have demonstrated promising results in both preclinical and clinical studies. Currently, several complement inhibitors are being developed for the treatment of complement-mediated renal diseases. This review aims to summarize the most recent insights into complement activation and therapeutic inhibition in renal diseases. Furthermore, it offers potential directions for the future rational use of complement inhibitor drugs in the context of renal diseases.
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Affiliation(s)
- Emma Diletta Stea
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), Nephrology and Urology Units, University of Bari Aldo Moro, Bari, Italy
| | | | - Adele Mitrotti
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), Nephrology and Urology Units, University of Bari Aldo Moro, Bari, Italy
| | - Loreto Gesualdo
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), Nephrology and Urology Units, University of Bari Aldo Moro, Bari, Italy.
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Li T, Yang K, Gao W, Peng F, Zou X. Cellular senescence in acute kidney injury: Target and opportunity. Biochem Biophys Res Commun 2024; 706:149744. [PMID: 38479244 DOI: 10.1016/j.bbrc.2024.149744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 02/28/2024] [Accepted: 02/29/2024] [Indexed: 03/24/2024]
Abstract
Acute kidney injury (AKI) is a common clinical disease with a high incidence and mortality rate. It typically arises from hemodynamic alterations, sepsis, contrast agents, and toxic drugs, instigating a series of events that culminate in tissue and renal damage. This sequence of processes often leads to acute renal impairment, prompting the initiation of a repair response. Cellular senescence is an irreversible arrest of the cell cycle. Studies have shown that renal cellular senescence is closely associated with AKI through several mechanisms, including the promotion of oxidative stress and inflammatory response, telomere shortening, and the down-regulation of klotho expression. Exploring the role of cellular senescence in AKI provides innovative therapeutic ideas for both the prevention and treatment of AKI. Furthermore, it has been observed that targeted removal of senescent cells in vivo can efficiently postpone senescence, resulting in an enhanced prognosis for diseases associated with senescence. This article explores the effects of common anti-senescence drugs senolytics and senostatic and lifestyle interventions on renal diseases, and mentions the rapid development of mesenchymal stem cells (MSCs). These studies have taken senescence-related research to a new level. Overall, this article comprehensively summarizes the studies on cellular senescence in AKI, aiming is to elucidate the relationship between cellular senescence and AKI, and explore treatment strategies to improve the prognosis of AKI.
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Affiliation(s)
- Ting Li
- School of Basic Medical Sciences, Shandong Second Medical University, Weifang, 261053, China.
| | - Kexin Yang
- School of Basic Medical Sciences, Shandong Second Medical University, Weifang, 261053, China
| | - Wei Gao
- School of Basic Medical Sciences, Shandong Second Medical University, Weifang, 261053, China
| | - Fujun Peng
- School of Basic Medical Sciences, Shandong Second Medical University, Weifang, 261053, China
| | - Xiangyu Zou
- School of Basic Medical Sciences, Shandong Second Medical University, Weifang, 261053, China.
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11
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Xie RC, Zhang JC, Lin XM, Huang T, Wang YT, Zhang LF, Hong XY, Lin XF, Zheng HJ, Luo Z, Yi LT, Ma JF. Inhibition of colon C5a/C5a receptor signalling pathway confers protection against LPS-induced acute kidney injury via gut microbiota-kidney axis. Eur J Pharmacol 2024; 969:176425. [PMID: 38387717 DOI: 10.1016/j.ejphar.2024.176425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 02/03/2024] [Accepted: 02/14/2024] [Indexed: 02/24/2024]
Abstract
Acute kidney injury (AKI) is a critical condition often associated with systemic inflammation and dysregulated gut microbiota. This study aimed to investigate the effects of the C5a receptor antagonist W54011 on lipopolysaccharide (LPS)-induced AKI, focusing on the colon's C5a/C5a receptor pathway, intestinal barrier integrity, and gut microbiota. Our findings demonstrate that W54011 effectively ameliorated kidney injury in the LPS-induced AKI model by selectively inhibiting the colon's C5a/C5a receptor signalling pathway. Additionally, C5a receptor blockade resulted in the inhibition of colonic inflammation and the reconstruction of the intestinal mucosal barrier. Furthermore, W54011 administration significantly impacted the composition and stability of the gut microbiota, restoring the abundance of dominant bacteria to levels observed in the normal state of the intestinal flora and reducing the abundance of potentially harmful bacterial groups. In conclusion, W54011 alleviates LPS-induced AKI by modulating the interplay between the colon, gut microbiota, and kidneys. It preserves the integrity of the intestinal barrier and reinstates gut microbiota, thereby mitigating AKI symptoms. These findings suggest that targeting the colon and gut microbiota could be a promising therapeutic strategy for AKI treatment.
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Affiliation(s)
- Rong-Cheng Xie
- Department of Critical Care Medicine, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, 361015, Fujian province, PR China
| | - Jin-Cheng Zhang
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200030, PR China
| | - Xiao-Ming Lin
- Department of Critical Care Medicine, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, 361015, Fujian province, PR China
| | - Ting Huang
- Department of Critical Care Medicine, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, 361015, Fujian province, PR China
| | - Yu-Ting Wang
- Department of Critical Care Medicine, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, 361015, Fujian province, PR China
| | - Lian-Fang Zhang
- Department of Critical Care Medicine, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, 361015, Fujian province, PR China
| | - Xiang-Yu Hong
- Department of Critical Care Medicine, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, 361015, Fujian province, PR China
| | - Xue-Feng Lin
- Department of Critical Care Medicine, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, 361015, Fujian province, PR China
| | - Hong-Jun Zheng
- Department of Critical Care Medicine, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, 361015, Fujian province, PR China
| | - Zhe Luo
- Cardiac Intensive Care Center, Zhongshan Hospital, Fudan University, Shanghai, 200030, PR China
| | - Li-Tao Yi
- Department of Chemical and Pharmaceutical Engineering, College of Chemical Engineering, Huaqiao University, Xiamen, 361021, Fujian province, PR China.
| | - Jie-Fei Ma
- Department of Critical Care Medicine, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, 361015, Fujian province, PR China.
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12
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Zhao X, Han J, Hu J, Qiu Z, Lu L, Xia C, Zheng Z, Zhang S. Association between albumin-corrected anion gap level and the risk of acute kidney injury in intensive care unit. Int Urol Nephrol 2024; 56:1117-1127. [PMID: 37642797 DOI: 10.1007/s11255-023-03755-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 08/16/2023] [Indexed: 08/31/2023]
Abstract
PURPOSE This study was to investigate the association between albumin-corrected anion gap (AG) (ACAG) levels and the risk of acute kidney injury (AKI) in intensive care unit (ICU) patients. METHODS The ICU patients of this retrospective cohort study were collected from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database between 2008 and 2019. ACAG = AG + {4.4 - [albumin (g/dl)]} × 2.5. The incidence of AKI was determined using the Kidney Disease: Improving Global Outcomes (KDIGO) definition. The logistic regression model was used to evaluate the association between ACAG levels and the risk of AKI. Subgroup analyses were applied based on age, gender, mechanical ventilation, vasopressors, the Charlson comorbidity index (CCI), and the Simplified Acute Physiology Score II (SAPS II). RESULTS Totally, 5586 patients were enrolled, of which 1929 patients (34.53%) occurred AKI. The higher levels of ACAG were associated with the risk of AKI in ICU patients, with the odds ratio (OR) value being 1.23 [95% confidence interval (CI): 1.22-1.24, P = 0.005] in ACAG level between 16.5 and 19.5, and OR value being 1.20 (95% CI 1.16-1.24, P = 0.016) in ACAG level > 19.5. A higher ACAG level was associated with a higher risk of AKI in ICU patients aged < 65 years, in ICU patients of female gender, in ICU patients who used mechanical ventilation, in ICU patients who did not use vasopressors, in patients without cardiogenic shock, and in ICU patients with CCI ≥ 2, and SAPS II > 31 (all P < 0.05). CONCLUSION There is an association between ACAG level and the risk of AKI in ICU patients. A higher ACAG value in ICU patients should therefore receive more attention.
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Affiliation(s)
- Xi Zhao
- Intensive Care Unit, Affiliated Hangzhou Xixi Hospital, Zhejiang University School of Medicine, 2 Hengbu Street, Liuhe Road, Xihu District, Hangzhou, 310023, People's Republic of China
| | - Jiayu Han
- Intensive Care Unit, Affiliated Hangzhou Xixi Hospital, Zhejiang University School of Medicine, 2 Hengbu Street, Liuhe Road, Xihu District, Hangzhou, 310023, People's Republic of China
| | - Jianliang Hu
- Intensive Care Unit, Affiliated Hangzhou Xixi Hospital, Zhejiang University School of Medicine, 2 Hengbu Street, Liuhe Road, Xihu District, Hangzhou, 310023, People's Republic of China
| | - Zhilei Qiu
- Intensive Care Unit, Affiliated Hangzhou Xixi Hospital, Zhejiang University School of Medicine, 2 Hengbu Street, Liuhe Road, Xihu District, Hangzhou, 310023, People's Republic of China
| | - Lihai Lu
- Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, People's Republic of China
| | - Chunxiao Xia
- Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, People's Republic of China
| | - Zihao Zheng
- Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, People's Republic of China
| | - Siquan Zhang
- Intensive Care Unit, Affiliated Hangzhou Xixi Hospital, Zhejiang University School of Medicine, 2 Hengbu Street, Liuhe Road, Xihu District, Hangzhou, 310023, People's Republic of China.
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13
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Terzioglu G, Young-Pearse TL. Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer's disease. Mol Neurodegener 2023; 18:89. [PMID: 38017562 PMCID: PMC10685641 DOI: 10.1186/s13024-023-00674-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 10/26/2023] [Indexed: 11/30/2023] Open
Abstract
Recent genetic studies on Alzheimer's disease (AD) have brought microglia under the spotlight, as loci associated with AD risk are enriched in genes expressed in microglia. Several of these genes have been recognized for their central roles in microglial functions. Increasing evidence suggests that SHIP1, the protein encoded by the AD-associated gene INPP5D, is an important regulator of microglial phagocytosis and immune response. A recent study from our group identified SHIP1 as a negative regulator of the NLRP3 inflammasome in human iPSC-derived microglial cells (iMGs). In addition, we found evidence for a connection between SHIP1 activity and inflammasome activation in the AD brain. The NLRP3 inflammasome is a multiprotein complex that induces the secretion of pro-inflammatory cytokines as part of innate immune responses against pathogens and endogenous damage signals. Previously published studies have suggested that the NLRP3 inflammasome is activated in AD and contributes to AD-related pathology. Here, we provide an overview of the current understanding of the microglial NLRP3 inflammasome in the context of AD-related inflammation. We then review the known intracellular functions of SHIP1, including its role in phosphoinositide signaling, interactions with microglial phagocytic receptors such as TREM2 and evidence for its intersection with NLRP3 inflammasome signaling. Through rigorous examination of the intricate connections between microglial signaling pathways across several experimental systems and postmortem analyses, the field will be better equipped to tailor newly emerging therapeutic strategies targeting microglia in neurodegenerative diseases.
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Affiliation(s)
- Gizem Terzioglu
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, 60 Fenwood Rd, Boston, MA, 02115, USA
| | - Tracy L Young-Pearse
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, 60 Fenwood Rd, Boston, MA, 02115, USA.
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14
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Lu Z, Xu S, Liao H, Zhang Y, Lu Z, Li Z, Chen Y, Guo F, Tang F, He Z. Identification of signature genes for renal ischemia‒reperfusion injury based on machine learning and WGCNA. Heliyon 2023; 9:e21151. [PMID: 37928383 PMCID: PMC10622618 DOI: 10.1016/j.heliyon.2023.e21151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Revised: 09/04/2023] [Accepted: 10/17/2023] [Indexed: 11/07/2023] Open
Abstract
Background As an inevitable event after kidney transplantation, ischemia‒reperfusion injury (IRI) can lead to a decrease in kidney transplant success. The search for signature genes of renal ischemia‒reperfusion injury (RIRI) is helpful in improving the diagnosis and guiding clinical treatment. Methods We first downloaded 3 datasets from the GEO database. Then, differentially expressed genes (DEGs) were identified and applied for functional enrichment analysis. After that, we performed three machine learning methods, including random forest (RF), Lasso regression analysis, and support vector machine recursive feature elimination (SVM-RFE), to further predict candidate genes. WGCNA was also executed to screen candidate genes from DEGs. Then, we took the intersection of candidate genes to obtain the signature genes of RIRI. Receiver operating characteristic (ROC) analysis was conducted to measure the predictive ability of the signature genes. Kaplan‒Meier analysis was used for association analysis between signature genes and graft survival. Verifying the expression of signature genes in the ischemia cell model. Results A total of 117 DEGs were screened out. Subsequently, RF, Lasso regression analysis, SVM-RFE and WGCNA identified 17, 25, 18 and 74 candidate genes, respectively. Finally, 3 signature genes (DUSP1, FOS, JUN) were screened out through the intersection of candidate genes. ROC analysis suggested that the 3 signature genes could well diagnose and predict RIRI. Kaplan‒Meier analysis indicated that patients with low FOS or JUN expression had a longer OS than those with high FOS or JUN expression. Finally, we validated using the ischemia cell model that compared to the control group, the expression level of JUN increased under hypoxic conditions. Conclusions Three signature genes (DUSP1, FOS, JUN) offer a good prediction for RIRI outcome and may serve as potential therapeutic targets for RIRI intervention, especially JUN. The prediction of graft survival by FOS and JUN may improve graft survival in patients with RIRI.
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Affiliation(s)
- Zechao Lu
- Department of Urology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, 518033, China
| | - Senkai Xu
- The Sixth Clinical College of Guangzhou Medical University, Guangzhou, Guangdong, 511436, China
| | - Haiqin Liao
- The Second Clinical College of Guangzhou Medical University, Guangzhou, Guangdong, 511436, China
| | - Yixin Zhang
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Clinical Research Center for Urological Diseases, Guangzhou, Guangdong, China
| | - Zeguang Lu
- The Second Clinical College of Guangzhou Medical University, Guangzhou, Guangdong, 511436, China
| | - Zhibiao Li
- Department of Urology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, 518033, China
| | - Yushu Chen
- Department of Urology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, 518033, China
| | - Feng Guo
- Department of Urology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, 518033, China
| | - Fucai Tang
- Department of Urology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, 518033, China
| | - Zhaohui He
- Department of Urology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, 518033, China
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15
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Zhang QQ, Zhang WJ, Chang S. HDAC6 inhibition: a significant potential regulator and therapeutic option to translate into clinical practice in renal transplantation. Front Immunol 2023; 14:1168848. [PMID: 37545520 PMCID: PMC10401441 DOI: 10.3389/fimmu.2023.1168848] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Accepted: 05/30/2023] [Indexed: 08/08/2023] Open
Abstract
Histone deacetylase 6 (HDAC6), an almost exclusively cytoplasmic enzyme, plays an essential role in many biological processes and exerts its deacetylation-dependent/independent effects on a variety of target molecules, which has contributed to the flourishing growth of relatively isoform-specific enzyme inhibitors. Renal transplantation (RT) is one of the alternatively preferred treatments and the most cost-effective treatment approaches for the great majority of patients with end-stage renal disease (ESRD). HDAC6 expression and activity have recently been shown to be increased in kidney disease in a number of studies. To date, a substantial amount of validated studies has identified HDAC6 as a pivotal modulator of innate and adaptive immunity, and HDAC6 inhibitors (HDAC6i) are being developed and investigated for use in arrays of immune-related diseases, making HDAC6i a promising therapeutic candidate for the management of a variety of renal diseases. Based on accumulating evidence, HDAC6i markedly open up new avenues for therapeutic intervention to protect against oxidative stress-induced damage, tip the balance in favor of the generation of tolerance-related immune cells, and attenuate fibrosis by inhibiting multiple activations of cell profibrotic signaling pathways. Taken together, we have a point of view that targeting HDAC6 may be a novel approach for the therapeutic strategy of RT-related complications, including consequences of ischemia-reperfusion injury, induction of immune tolerance in transplantation, equilibrium of rejection, and improvement of chronic renal graft interstitial fibrosis after transplantation in patients. Herein, we will elaborate on the unique function of HDAC6, which focuses on therapeutical mechanism of action related to immunological events with a general account of the tantalizing potential to the clinic.
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Affiliation(s)
- Qian-qian Zhang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Wei-jie Zhang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Sheng Chang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
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16
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Fiorentino M, Bagagli F, Deleonardis A, Stasi A, Franzin R, Conserva F, Infante B, Stallone G, Pontrelli P, Gesualdo L. Acute Kidney Injury in Kidney Transplant Patients in Intensive Care Unit: From Pathogenesis to Clinical Management. Biomedicines 2023; 11:1474. [PMID: 37239144 PMCID: PMC10216683 DOI: 10.3390/biomedicines11051474] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 05/05/2023] [Accepted: 05/16/2023] [Indexed: 05/28/2023] Open
Abstract
Kidney transplantation is the first-choice treatment for end-stage renal disease (ESRD). Kidney transplant recipients (KTRs) are at higher risk of experiencing a life-threatening event requiring intensive care unit (ICU) admission, mainly in the late post-transplant period (more than 6 months after transplantation). Urosepsis and bloodstream infections account for almost half of ICU admissions in this population; in addition, potential side effects related to immunosuppressive treatment should be accounted for cytotoxic and ischemic changes induced by calcineurin inhibitor (CNI), sirolimus/CNI-induced thrombotic microangiopathy and posterior reversible encephalopathy syndrome. Throughout the ICU stay, Acute Kidney Injury (AKI) incidence is common and ranges from 10% to 80%, and up to 40% will require renal replacement therapy. In-hospital mortality can reach 30% and correlates with acute illness severity and admission diagnosis. Graft survival is subordinated to baseline estimated glomerular filtration rate (eGFR), clinical presentation, disease severity and potential drug nephrotoxicity. The present review aims to define the impact of AKI events on short- and long-term outcomes in KTRs, focusing on the epidemiologic data regarding AKI incidence in this subpopulation; the pathophysiological mechanisms underlying AKI development and potential AKI biomarkers in kidney transplantation, graft and patients' outcomes; the current diagnostic work up and management of AKI; and the modulation of immunosuppression in ICU-admitted KTRs.
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Affiliation(s)
- Marco Fiorentino
- Nephrology, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari “Aldo Moro”, 70121 Bari, Italy; (M.F.)
| | - Francesca Bagagli
- Nephrology, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari “Aldo Moro”, 70121 Bari, Italy; (M.F.)
| | - Annamaria Deleonardis
- Nephrology, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari “Aldo Moro”, 70121 Bari, Italy; (M.F.)
| | - Alessandra Stasi
- Nephrology, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari “Aldo Moro”, 70121 Bari, Italy; (M.F.)
| | - Rossana Franzin
- Nephrology, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari “Aldo Moro”, 70121 Bari, Italy; (M.F.)
| | - Francesca Conserva
- Nephrology, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari “Aldo Moro”, 70121 Bari, Italy; (M.F.)
| | - Barbara Infante
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Science, University of Foggia, 71122 Foggia, Italy
| | - Giovanni Stallone
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Science, University of Foggia, 71122 Foggia, Italy
| | - Paola Pontrelli
- Nephrology, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari “Aldo Moro”, 70121 Bari, Italy; (M.F.)
| | - Loreto Gesualdo
- Nephrology, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari “Aldo Moro”, 70121 Bari, Italy; (M.F.)
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17
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Yang G, Tan L, Yao H, Xiong Z, Wu J, Huang X. Long-Term Effects of Severe Burns on the Kidneys: Research Advances and Potential Therapeutic Approaches. J Inflamm Res 2023; 16:1905-1921. [PMID: 37152866 PMCID: PMC10162109 DOI: 10.2147/jir.s404983] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 04/14/2023] [Indexed: 05/09/2023] Open
Abstract
Burns are a seriously underestimated form of trauma that not only damage the skin system but also cause various complications, such as acute kidney injury (AKI). Recent clinical studies have shown that the proportion of chronic kidney diseases (CKD) in burn patients after discharge is significantly higher than that in the general population, but the mechanism behind this is controversial. The traditional view is that CKD is associated with hypoperfusion, AKI, sepsis, and drugs administered in the early stages of burns. However, recent studies have shown that burns can cause long-term immune dysfunction, which is a high-risk factor for CKD. This suggests that burns affect the kidneys more than previously recognized. In other words, severe burns are not only an acute injury but also a chronic disease. Neglecting to study long-term kidney function in burn patients also results in a lack of preventive and therapeutic methods being developed. Furthermore, stem cells and their exosomes have shown excellent comprehensive therapeutic properties in the prevention and treatment of CKD, making them increasingly the focus of research attention. Their engineering strategy further improved the therapeutic performance. This review will focus on the research advances in burns on the development of CKD, illustrating the possible mechanism of burn-induced CKD and introducing potential biological treatment options and their engineering strategies.
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Affiliation(s)
- Guang Yang
- Division of Renal Medicine, Peking University Shenzhen Hospital, Peking University, Shenzhen, 518000, People’s Republic of China
- Department of Life Sciences, Yuncheng University, Yuncheng, 044006, People’s Republic of China
| | - Lishan Tan
- Division of Renal Medicine, Peking University Shenzhen Hospital, Peking University, Shenzhen, 518000, People’s Republic of China
| | - Hua Yao
- Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical College, Guilin, 541004, People’s Republic of China
| | - Zuying Xiong
- Division of Renal Medicine, Peking University Shenzhen Hospital, Peking University, Shenzhen, 518000, People’s Republic of China
| | - Jun Wu
- Department of Burn and Plastic Surgery, Shenzhen Institute of Translational Medicine, Shenzhen Second People’s Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen, 518035, People’s Republic of China
- Human Histology & Embryology Section, Department of Surgery, Dentistry, Pediatrics & Gynecology, University of Verona Medical School, Verona, Venetia, 37134, Italy
| | - Xiaoyan Huang
- Division of Renal Medicine, Peking University Shenzhen Hospital, Peking University, Shenzhen, 518000, People’s Republic of China
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18
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Santarsiero D, Aiello S. The Complement System in Kidney Transplantation. Cells 2023; 12:cells12050791. [PMID: 36899927 PMCID: PMC10001167 DOI: 10.3390/cells12050791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Revised: 02/24/2023] [Accepted: 02/27/2023] [Indexed: 03/06/2023] Open
Abstract
Kidney transplantation is the therapy of choice for patients who suffer from end-stage renal diseases. Despite improvements in surgical techniques and immunosuppressive treatments, long-term graft survival remains a challenge. A large body of evidence documented that the complement cascade, a part of the innate immune system, plays a crucial role in the deleterious inflammatory reactions that occur during the transplantation process, such as brain or cardiac death of the donor and ischaemia/reperfusion injury. In addition, the complement system also modulates the responses of T cells and B cells to alloantigens, thus playing a crucial role in cellular as well as humoral responses to the allograft, which lead to damage to the transplanted kidney. Since several drugs that are capable of inhibiting complement activation at various stages of the complement cascade are emerging and being developed, we will discuss how these novel therapies could have potential applications in ameliorating outcomes in kidney transplantations by preventing the deleterious effects of ischaemia/reperfusion injury, modulating the adaptive immune response, and treating antibody-mediated rejection.
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19
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Kasravi M, Ahmadi A, Babajani A, Mazloomnejad R, Hatamnejad MR, Shariatzadeh S, Bahrami S, Niknejad H. Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine. Biomater Res 2023; 27:10. [PMID: 36759929 PMCID: PMC9912640 DOI: 10.1186/s40824-023-00348-z] [Citation(s) in RCA: 79] [Impact Index Per Article: 39.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 01/30/2023] [Indexed: 02/11/2023] Open
Abstract
Tissue-engineered decellularized extracellular matrix (ECM) scaffolds hold great potential to address the donor shortage as well as immunologic rejection attributed to cells in conventional tissue/organ transplantation. Decellularization, as the key process in manufacturing ECM scaffolds, removes immunogen cell materials and significantly alleviates the immunogenicity and biocompatibility of derived scaffolds. However, the application of these bioscaffolds still confronts major immunologic challenges. This review discusses the interplay between damage-associated molecular patterns (DAMPs) and antigens as the main inducers of innate and adaptive immunity to aid in manufacturing biocompatible grafts with desirable immunogenicity. It also appraises the impact of various decellularization methodologies (i.e., apoptosis-assisted techniques) on provoking immune responses that participate in rejecting allogenic and xenogeneic decellularized scaffolds. In addition, the key research findings regarding the contribution of ECM alterations, cytotoxicity issues, graft sourcing, and implantation site to the immunogenicity of decellularized tissues/organs are comprehensively considered. Finally, it discusses practical solutions to overcome immunogenicity, including antigen masking by crosslinking, sterilization optimization, and antigen removal techniques such as selective antigen removal and sequential antigen solubilization.
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Affiliation(s)
- Mohammadreza Kasravi
- grid.411600.2Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 1985711151 Iran ,grid.411600.2Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Armin Ahmadi
- grid.411600.2Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 1985711151 Iran
| | - Amirhesam Babajani
- grid.411600.2Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 1985711151 Iran
| | - Radman Mazloomnejad
- grid.411600.2Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 1985711151 Iran
| | - Mohammad Reza Hatamnejad
- grid.411600.2Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Siavash Shariatzadeh
- grid.19006.3e0000 0000 9632 6718Department of Surgery, University of California Los Angeles, Los Angeles, California USA
| | - Soheyl Bahrami
- grid.454388.60000 0004 6047 9906Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in AUVA Research Center, Vienna, Austria
| | - Hassan Niknejad
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 1985711151, Iran.
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20
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A. Eid R, Alaa Edeen M, Soltan MA, Al-Shraim M, Samir A. Zaki M, M. Al-Qahtani S, Fayad E, T. Salem E, K. Abdulsahib W, Emam H, M. Hassan H. Integration of Ultrastructural and Computational Approaches Reveals the Protective Effect of Astaxanthin against BPA-Induced Nephrotoxicity. Biomedicines 2023; 11:biomedicines11020421. [PMID: 36830956 PMCID: PMC9953522 DOI: 10.3390/biomedicines11020421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Revised: 01/19/2023] [Accepted: 01/22/2023] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Bisphenol A (BPA) is an environmental contaminant that can induce deleterious organ effects. Human Cytochrome P450 CYP2C9 enzyme belongs to the essential xenobiotic-metabolizing enzymes, producing ROS as a byproduct. Astaxanthin (ATX) is a powerful antioxidant that protects organs and tissues from the damaging effects of oxidative stress caused by various diseases. AIM OF THE STUDY This study investigated the possible protective impacts of ATX against BPA-induced nephrotoxicity and its underlying mechanism. MATERIALS AND METHODS Kidney tissues were isolated and examined microscopically from control, protected, and unprotected groups of rats to examine the potential protective effect of ATX against nephrotoxicity. Moreover, a molecular dynamic (MD) simulation was conducted to predict the performance of ATX upon binding to the active site of P450 CYP2C9 protein receptor as a potential mechanism of ATX protective effect. RESULTS Implemented computational methods revealed the possible underlying mechanism of ATX protection; the protective impact of ATX is mediated by inhibiting P450 CYP2C9 through binding to its dimeric state where the RMSF value for apo-protein and ATX-complex system were 5.720.57 and 1.040.41, respectively, implicating the ATX-complex system to have lesser variance in its residues, leading to the prevention of ROS excess production, maintaining the oxidant-antioxidant balance and re-establishing the proper mitochondrial functionality. Furthermore, the experimental methods validated in silico outcomes and revealed that ATX therapy effectively restored the typical histological architecture of pathological kidney tissues. CONCLUSIONS ATX prevents BPA-induced nephrotoxicity by controlling oxidative imbalance and reversing mitochondrial dysfunction. These outcomes shed new light on the appropriate use of ATX as a treatment or prophylactic agent for these severe conditions.
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Affiliation(s)
- Refaat A. Eid
- Pathology Department, College of Medicine, King Khalid University, Abha P.O. Box 62529, Saudi Arabia
- Correspondence: (R.A.E.); (M.A.E.)
| | - Muhammad Alaa Edeen
- Cell Biology, Histology & Genetics Division, Biology Department, Faculty of Science, Zagazig University, Zagazig 44519, Egypt
- Correspondence: (R.A.E.); (M.A.E.)
| | - Mohamed A. Soltan
- Department of Microbiology and Immunology, Faculty of Pharmacy, Sinai University, Ismailia 41611, Egypt
| | - Mubarak Al-Shraim
- Pathology Department, College of Medicine, King Khalid University, Abha P.O. Box 62529, Saudi Arabia
| | - Mohamed Samir A. Zaki
- Anatomy Department, College of Medicine, King Khalid University, Abha P.O. Box 62529, Saudi Arabia
- Department of Histology and Cell Biology, College of Medicine, Zagazig University, Zagazig 31527, Egypt
| | - Saleh M. Al-Qahtani
- Department of Child Health, College of Medicine, King Khalid University, Abha P.O. Box 62529, Saudi Arabia
| | - Eman Fayad
- Department of Biotechnology, College of Sciences, Taif University, Taif 21944, Saudi Arabia
| | - Eman T. Salem
- Department of Basic Science, Faculty of Physical Therapy, Horus University-Egypt, New Damietta 34518, Egypt
| | - Waleed K. Abdulsahib
- Pharmacology and Toxicology Department, College of Pharmacy, Al-Farahidi University, Baghdad 10001, Iraq
| | - Hebatallah Emam
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Benha University, Benha 13518, Egypt
| | - Hesham M. Hassan
- Pathology Department, College of Medicine, King Khalid University, Abha P.O. Box 62529, Saudi Arabia
- Department of Pathology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt
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Stasi A, Franzin R, Caggiano G, Losapio R, Fiorentino M, Alfieri C, Gesualdo L, Stallone G, Castellano G. New Frontiers in Sepsis-Induced Acute Kidney Injury and Blood Purification Therapies: The Role of Polymethylmethacrylate Membrane Hemofilter. Blood Purif 2023; 52 Suppl 1:71-84. [PMID: 36693337 PMCID: PMC10210082 DOI: 10.1159/000528685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Accepted: 11/17/2022] [Indexed: 01/25/2023]
Abstract
Acute kidney injury (AKI) is a common consequence of sepsis with a mortality rate of up to 40%. The pathogenesis of septic AKI is complex and involves several mechanisms leading to exacerbated inflammatory response associated with renal injury. A large body of evidence suggests that inflammation is tightly linked to AKI through bidirectional interaction between renal and immune cells. Preclinical data from our and other laboratories have identified in complement system activation a crucial mediator of AKI. Partial recovery following AKI could lead to long-term consequences that predispose to chronic dysfunction and may also accelerate the progression of preexisting chronic kidney disease. Recent findings have revealed striking morphological and functional changes in renal parenchymal cells induced by mitochondrial dysfunction, cell cycle arrest via the activation of signaling pathways involved in aging process, microvascular rarefaction, and early fibrosis. Although major advances have been made in our understanding of the pathophysiology of AKI, there are no available preventive and therapeutic strategies in this field. The identification of ideal clinical biomarkers for AKI enables prompt and effective therapeutic strategy that could prevent the progression of renal injury and promote repair process. Therefore, the use of novel biomarkers associated with clinical and functional criteria could provide early interventions and better outcome. Several new drugs for AKI are currently being investigated; however, the complexity of this disease might explain the failure of pharmacological intervention targeting just one of the many systems involved. The hypothesis that blood purification could improve the outcome of septic AKI has attracted much attention. New relevant findings on the role of polymethylmethacrylate-based continuous veno-venous hemofiltration in septic AKI have been reported. Herein, we provide a comprehensive literature review on advances in the pathophysiology of septic AKI and potential therapeutic approaches in this field.
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Affiliation(s)
- Alessandra Stasi
- Renal, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DIMEPRE-J), University of Bari, Bari, Italy
| | - Rossana Franzin
- Renal, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DIMEPRE-J), University of Bari, Bari, Italy
| | - Gianvito Caggiano
- Renal, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DIMEPRE-J), University of Bari, Bari, Italy
| | - Rosa Losapio
- Renal, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DIMEPRE-J), University of Bari, Bari, Italy
| | - Marco Fiorentino
- Renal, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DIMEPRE-J), University of Bari, Bari, Italy
| | - Carlo Alfieri
- Nephrology, Dialysis and Renal Transplant Unit, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Loreto Gesualdo
- Renal, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DIMEPRE-J), University of Bari, Bari, Italy
| | - Giovanni Stallone
- Nephrology Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, Advanced Research Center on Kidney Aging (A.R.K.A.), University of Foggia, Foggia, Italy
| | - Giuseppe Castellano
- Nephrology, Dialysis and Renal Transplant Unit, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
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22
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Valproic acid attenuates cellular senescence in diabetic kidney disease through the inhibition of complement C5a receptors. Sci Rep 2022; 12:20278. [PMID: 36434087 PMCID: PMC9700697 DOI: 10.1038/s41598-022-24851-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 11/21/2022] [Indexed: 11/27/2022] Open
Abstract
Despite increasing knowledge about the factors involved in the progression of diabetic complications, diabetic kidney disease (DKD) continues to be a major health burden. Current therapies only slow but do not prevent the progression of DKD. Thus, there is an urgent need to develop novel therapy to halt the progression of DKD and improve disease prognosis. In our preclinical study where we administered a histone deacetylase (HDAC) inhibitor, valproic acid, to streptozotocin-induced diabetic mice, albuminuria and glomerulosclerosis were attenuated. Furthermore, we discovered that valproic acid attenuated diabetes-induced upregulation of complement C5a receptors, with a concomitant reduction in markers of cellular senescence and senescence-associated secretory phenotype. Interestingly, further examination of mice lacking the C5a receptor 1 (C5aR1) gene revealed that cellular senescence was attenuated in diabetes. Similar results were observed in diabetic mice treated with a C5aR1 inhibitor, PMX53. RNA-sequencing analyses showed that PMX53 significantly regulated genes associated with cell cycle pathways leading to cellular senescence. Collectively, these results for the first time demonstrated that complement C5a mediates cellular senescence in diabetic kidney disease. Cellular senescence has been implicated in the pathogenesis of diabetic kidney disease, thus therapies to inhibit cellular senescence such as complement inhibitors present as a novel therapeutic option to treat diabetic kidney disease.
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23
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Wang K, Qi L, Zhao L, Liu J, Guo Y, Zhang C. Degradation of chondroitin sulfate: Mechanism of degradation, influence factors, structure-bioactivity relationship and application. Carbohydr Polym 2022; 301:120361. [PMID: 36446498 DOI: 10.1016/j.carbpol.2022.120361] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 11/12/2022] [Accepted: 11/13/2022] [Indexed: 11/19/2022]
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24
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Brandwijk RJMGE, Michels MAHM, van Rossum M, de Nooijer AH, Nilsson PH, de Bruin WCC, Toonen EJM. Pitfalls in complement analysis: A systematic literature review of assessing complement activation. Front Immunol 2022; 13:1007102. [PMID: 36330514 PMCID: PMC9623276 DOI: 10.3389/fimmu.2022.1007102] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 09/13/2022] [Indexed: 11/13/2022] Open
Abstract
Background The complement system is an essential component of our innate defense and plays a vital role in the pathogenesis of many diseases. Assessment of complement activation is critical in monitoring both disease progression and response to therapy. Complement analysis requires accurate and standardized sampling and assay procedures, which has proven to be challenging. Objective We performed a systematic analysis of the current methods used to assess complement components and reviewed whether the identified studies performed their complement measurements according to the recommended practice regarding pre-analytical sample handling and assay technique. Results are supplemented with own data regarding the assessment of key complement biomarkers to illustrate the importance of accurate sampling and measuring of complement components. Methods A literature search using the Pubmed/MEDLINE database was performed focusing on studies measuring the key complement components C3, C5 and/or their split products and/or the soluble variant of the terminal C5b-9 complement complex (sTCC) in human blood samples that were published between February 2017 and February 2022. The identified studies were reviewed whether they had used the correct sample type and techniques for their analyses. Results A total of 92 out of 376 studies were selected for full-text analysis. Forty-five studies (49%) were identified as using the correct sample type and techniques for their complement analyses, while 25 studies (27%) did not use the correct sample type or technique. For 22 studies (24%), it was not specified which sample type was used. Conclusion A substantial part of the reviewed studies did not use the appropriate sample type for assessing complement activation or did not mention which sample type was used. This deviation from the standardized procedure can lead to misinterpretation of complement biomarker levels and hampers proper comparison of complement measurements between studies. Therefore, this study underlines the necessity of general guidelines for accurate and standardized complement analysis
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Affiliation(s)
| | - Marloes A. H. M. Michels
- Radboud Institute for Molecular Life Sciences, Department of Pediatric Nephrology, Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, Netherlands
| | - Mara van Rossum
- R&D Department, Hycult Biotechnology b.v., Uden, Netherlands
| | - Aline H. de Nooijer
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands
| | - Per H. Nilsson
- Department of Immunology, University of Oslo and Oslo University Hospital Rikshospitalet, Oslo, Norway
- Linnaeus Centre for Biomaterials Chemistry, Linnaeus University, Kalmar, Sweden
- Department of Chemistry and Biomedical Sciences, Linnaeus University, Kalmar, Sweden
| | | | - Erik J. M. Toonen
- R&D Department, Hycult Biotechnology b.v., Uden, Netherlands
- *Correspondence: Erik J. M. Toonen,
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25
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Cellular senescence in ischemia/reperfusion injury. Cell Death Dis 2022; 8:420. [PMID: 36253355 PMCID: PMC9576687 DOI: 10.1038/s41420-022-01205-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 09/22/2022] [Accepted: 09/27/2022] [Indexed: 11/24/2022]
Abstract
Ischemia/reperfusion (IR) injury, a main reason of mortality and morbidity worldwide, occurs in many organs and tissues. As a result of IR injury, senescent cells can accumulate in multiple organs. Increasing evidence shows that cellular senescence is the underlying mechanism that transforms an acute organ injury into a chronic one. Several recent studies suggest senescent cells can be targeted for the prevention or elimination of acute and chronic organ injury induced by IR. In this review, we concisely introduce the underlying mechanism and the pivotal role of premature senescence in the transition from acute to chronic IR injuries. Special focus is laid on recent advances in the mechanisms as well as on the basic and clinical research, targeting cellular senescence in multi-organ IR injuries. Besides, the potential directions in this field are discussed in the end. Together, the recent advances reviewed here will act as a comprehensive overview of the roles of cellular senescence in IR injury, which could be of great significance for the design of related studies, or as a guide for potential therapeutic target.
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26
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Quaglia M, Fanelli V, Merlotti G, Costamagna A, Deregibus MC, Marengo M, Balzani E, Brazzi L, Camussi G, Cantaluppi V. Dual Role of Extracellular Vesicles in Sepsis-Associated Kidney and Lung Injury. Biomedicines 2022; 10:biomedicines10102448. [PMID: 36289710 PMCID: PMC9598620 DOI: 10.3390/biomedicines10102448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 09/25/2022] [Accepted: 09/27/2022] [Indexed: 11/16/2022] Open
Abstract
Extracellular vesicles form a complex intercellular communication network, shuttling a variety of proteins, lipids, and nucleic acids, including regulatory RNAs, such as microRNAs. Transfer of these molecules to target cells allows for the modulation of sets of genes and mediates multiple paracrine and endocrine actions. EVs exert broad pro-inflammatory, pro-oxidant, and pro-apoptotic effects in sepsis, mediating microvascular dysfunction and multiple organ damage. This deleterious role is well documented in sepsis-associated acute kidney injury and acute respiratory distress syndrome. On the other hand, protective effects of stem cell-derived extracellular vesicles have been reported in experimental models of sepsis. Stem cell-derived extracellular vesicles recapitulate beneficial cytoprotective, regenerative, and immunomodulatory properties of parental cells and have shown therapeutic effects in experimental models of sepsis with kidney and lung involvement. Extracellular vesicles are also likely to play a role in deranged kidney-lung crosstalk, a hallmark of sepsis, and may be key to a better understanding of shared mechanisms underlying multiple organ dysfunction. In this review, we analyze the state-of-the-art knowledge on the dual role of EVs in sepsis-associated kidney/lung injury and repair. PubMed library was searched from inception to July 2022, using a combination of medical subject headings (MeSH) and keywords related to EVs, sepsis, acute kidney injury (AKI), acute lung injury (ALI), and acute respiratory distress syndrome (ARDS). Key findings are summarized into two sections on detrimental and beneficial mechanisms of actions of EVs in kidney and lung injury, respectively. The role of EVs in kidney-lung crosstalk is then outlined. Efforts to expand knowledge on EVs may pave the way to employ them as prognostic biomarkers or therapeutic targets to prevent or reduce organ damage in sepsis.
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Affiliation(s)
- Marco Quaglia
- Nephrology and Kidney Transplantation Unit, Department of Translational Medicine, University of Piemonte Orientale (UPO), 28100 Novara, Italy
| | - Vito Fanelli
- Department of Anaesthesia, Critical Care and Emergency, Città della Salute e della Scienza Hospital, University of Torino, 10126 Torino, Italy
| | - Guido Merlotti
- Nephrology and Kidney Transplantation Unit, Department of Translational Medicine, University of Piemonte Orientale (UPO), 28100 Novara, Italy
| | - Andrea Costamagna
- Department of Anaesthesia, Critical Care and Emergency, Città della Salute e della Scienza Hospital, University of Torino, 10126 Torino, Italy
| | | | - Marita Marengo
- Nephrology and Dialysis Unit, ASL CN1, 12038 Savigliano, Italy
| | - Eleonora Balzani
- Department of Anaesthesia, Critical Care and Emergency, Città della Salute e della Scienza Hospital, University of Torino, 10126 Torino, Italy
| | - Luca Brazzi
- Department of Anaesthesia, Critical Care and Emergency, Città della Salute e della Scienza Hospital, University of Torino, 10126 Torino, Italy
| | - Giovanni Camussi
- Department of Medical Sciences, University of Torino, 10126 Torino, Italy
- Correspondence: (G.C.); (V.C.)
| | - Vincenzo Cantaluppi
- Nephrology and Kidney Transplantation Unit, Department of Translational Medicine, University of Piemonte Orientale (UPO), 28100 Novara, Italy
- Correspondence: (G.C.); (V.C.)
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Zhao S, Liu Y, Zhou C, Chen Z, Cai Z, Han J, Xiao J, Xiao Q. Prediction model of delayed graft function based on clinical characteristics combined with serum IL-2 levels. BMC Nephrol 2022; 23:284. [PMID: 35971094 PMCID: PMC9377118 DOI: 10.1186/s12882-022-02908-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 08/04/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Kidney transplantation is an effective treatment for end-stage renal disease (ESRD). Delayed graft function (DGF) is a common complication after kidney transplantation and exerts substantial effects on graft function and long-term graft survival. Therefore, the construction of an effective model to predict the occurrence of DGF is particularly important. METHODS Seventy-one patients receiving their first kidney transplant at the First Affiliated Hospital of Nanchang University from October 2020 to October 2021 were enrolled in the discovery cohort. Based on clinical characteristics and serum markers, a logistic regression model was used to simulate the risk of DGF in the discovery cohort. The DGF prediction model was named the prediction system and was composed of risk factors related to DGF. Thirty-two patients receiving a kidney transplant at the First Affiliated Hospital of Nanchang University from October 2021 to February 2022 were enrolled in the validation cohort. The validation cohort was used to verify the accuracy and reliability of the prediction model. RESULTS Cold ischemia time (CIT), donor history of diabetes mellitus, donor interleukin-2 (IL-2) level and donor terminal creatinine level constitute the prediction system. In the validation test, the area under the receiver operating characteristic curve (AUC) was 0.867 for the prediction system, and good calibration of the model was confirmed in the validation cohort. CONCLUSIONS This study constructed a reliable and highly accurate prediction model that provides a practical tool for predicting DGF. Additionally, IL-2 participates in the kidney injury process and may be a potential marker of kidney injury.
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Affiliation(s)
- Shitao Zhao
- Department of Transplantation, The First Affiliated Hospital of Nanchang University, 17 Yongwai Zhengjie Street, Nanchang, 330006, Jiangxi, China
| | - Yuan Liu
- Department of Transplantation, The First Affiliated Hospital of Nanchang University, 17 Yongwai Zhengjie Street, Nanchang, 330006, Jiangxi, China
| | - Chen Zhou
- Department of Transplantation, The First Affiliated Hospital of Nanchang University, 17 Yongwai Zhengjie Street, Nanchang, 330006, Jiangxi, China
| | - Zide Chen
- Department of Transplantation, The First Affiliated Hospital of Nanchang University, 17 Yongwai Zhengjie Street, Nanchang, 330006, Jiangxi, China
| | - Zeyu Cai
- Department of Transplantation, The First Affiliated Hospital of Nanchang University, 17 Yongwai Zhengjie Street, Nanchang, 330006, Jiangxi, China
| | - JiaLiang Han
- Department of Transplantation, The First Affiliated Hospital of Nanchang University, 17 Yongwai Zhengjie Street, Nanchang, 330006, Jiangxi, China
| | - Jiansheng Xiao
- Department of Transplantation, The First Affiliated Hospital of Nanchang University, 17 Yongwai Zhengjie Street, Nanchang, 330006, Jiangxi, China.
| | - Qi Xiao
- Department of Transplantation, The First Affiliated Hospital of Nanchang University, 17 Yongwai Zhengjie Street, Nanchang, 330006, Jiangxi, China.
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28
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Dumbill R, Jaques R, Robb M, Johnson R, Ploeg RJ, Kaisar ME, Sharples EJ. Transplant and Recipient Factors in Prediction of Kidney Transplant Outcomes: A UK-Wide Paired Analysis. J Clin Med 2022; 11:jcm11082222. [PMID: 35456312 PMCID: PMC9024822 DOI: 10.3390/jcm11082222] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 04/08/2022] [Accepted: 04/12/2022] [Indexed: 12/03/2022] Open
Abstract
Background: In kidney transplantation, the relative contribution of various donor, procedure and recipient-related factors on clinical outcomes is unknown. Previous paired studies have largely focused on examining factors predicting early outcomes, where the effect of donor factors is thought to be most important. Here, we sought to examine the relationship between early and long-term outcomes in a UK-wide paired kidney analysis. Methods: UK Transplant Registry data covering 24,090 kidney transplants performed between 2001–2018, where both kidneys from each donor were transplanted, were analysed. Case-control studies were constructed using matched pairs of kidneys from the same donor discordant for outcome, to delineate the impact of transplant and recipient factors on longer-term outcomes. Results: Multivariable conditional logistic regression identified HLA mismatch as an important predictor of prolonged delayed graft function (DGF), in the context of a paired study controlling for the influence of donor factors, even when adjusting for early acute rejection. Prolonged DGF, but not human leucocyte antigen (HLA) mismatch, strongly predicted 12-month graft function, and impaired 12-month graft function was associated with an increased risk of graft failure. Conclusions: This study indicates prolonged DGF is associated with adverse long-term outcomes and suggests that alloimmunity may contribute to prolonged DGF by a mechanism distinct from typical early acute rejection.
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Affiliation(s)
- Richard Dumbill
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 9DU, UK; (R.J.P.); (M.E.K.)
- Oxford Transplant Unit, Oxford University Hospitals, Oxford OX3 7LE, UK;
- Correspondence:
| | - Roderick Jaques
- Statistics and Clinical Studies, NHS Blood and Transplant, Bristol BS34 7QH, UK; (R.J.); (M.R.); (R.J.)
| | - Matthew Robb
- Statistics and Clinical Studies, NHS Blood and Transplant, Bristol BS34 7QH, UK; (R.J.); (M.R.); (R.J.)
| | - Rachel Johnson
- Statistics and Clinical Studies, NHS Blood and Transplant, Bristol BS34 7QH, UK; (R.J.); (M.R.); (R.J.)
| | - Rutger J. Ploeg
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 9DU, UK; (R.J.P.); (M.E.K.)
- Research and Development, NHS Blood and Transplant, Oxford OX3 9DU, UK
| | - Maria E. Kaisar
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 9DU, UK; (R.J.P.); (M.E.K.)
- Research and Development, NHS Blood and Transplant, Oxford OX3 9DU, UK
| | - Edward J. Sharples
- Oxford Transplant Unit, Oxford University Hospitals, Oxford OX3 7LE, UK;
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Quaglia M, Merlotti G, Colombatto A, Bruno S, Stasi A, Franzin R, Castellano G, Grossini E, Fanelli V, Cantaluppi V. Stem Cell-Derived Extracellular Vesicles as Potential Therapeutic Approach for Acute Kidney Injury. Front Immunol 2022; 13:849891. [PMID: 35359949 PMCID: PMC8960117 DOI: 10.3389/fimmu.2022.849891] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 02/15/2022] [Indexed: 12/12/2022] Open
Abstract
Acute kidney injury is a frequent complication of hospitalized patients and significantly increases morbidity and mortality, worsening costs and length of hospital stay. Despite this impact on healthcare system, treatment still remains only supportive (dialysis). Stem cell-derived extracellular vesicles are a promising option as they recapitulate stem cells properties, overcoming safety issues related to risks or rejection or aberrant differentiation. A growing body of evidence based on pre-clinical studies suggests that extracellular vesicles may be effective to treat acute kidney injury and to limit fibrosis through direct interference with pathogenic mechanisms of vascular and tubular epithelial cell damage. We herein analyze the state-of-the-art knowledge of therapeutic approaches with stem cell-derived extracellular vesicles for different forms of acute kidney injury (toxic, ischemic or septic) dissecting their cytoprotective, regenerative and immunomodulatory properties. We also analyze the potential impact of extracellular vesicles on the mechanisms of transition from acute kidney injury to chronic kidney disease, with a focus on the pivotal role of the inhibition of complement cascade in this setting. Despite some technical limits, nowadays the development of therapies based on stem cell-derived extracellular vesicles holds promise as a new frontier to limit acute kidney injury onset and progression.
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Affiliation(s)
- Marco Quaglia
- Nephrology and Kidney Transplantation Unit, "Maggiore della Carità" University Hospital, Department of Translational Medicine, Translational Research on Autoimmune and Allergic Disease (CAAD), University of Piemonte Orientale (UPO), Novara, Italy
| | - Guido Merlotti
- Nephrology and Kidney Transplantation Unit, "Maggiore della Carità" University Hospital, Department of Translational Medicine, Translational Research on Autoimmune and Allergic Disease (CAAD), University of Piemonte Orientale (UPO), Novara, Italy
| | - Andrea Colombatto
- Nephrology and Kidney Transplantation Unit, "Maggiore della Carità" University Hospital, Department of Translational Medicine, Translational Research on Autoimmune and Allergic Disease (CAAD), University of Piemonte Orientale (UPO), Novara, Italy
| | - Stefania Bruno
- Department of Medical Sciences, University of Torino, Torino, Italy
| | - Alessandra Stasi
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| | - Rossana Franzin
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| | - Giuseppe Castellano
- Nephrology, Dialysis and Kidney Transplantation Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Elena Grossini
- Laboratory of Physiology, Department of Translational Medicine, Translational Research on Autoimmune and Allergic Disease (CAAD), University of Piemonte Orientale, Novara, Italy
| | - Vito Fanelli
- Department of Anesthesiology and Intensive Care, University of Torino, Torino, Italy
| | - Vincenzo Cantaluppi
- Nephrology and Kidney Transplantation Unit, "Maggiore della Carità" University Hospital, Department of Translational Medicine, Translational Research on Autoimmune and Allergic Disease (CAAD), University of Piemonte Orientale (UPO), Novara, Italy
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30
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Di Zazzo A, Coassin M, Surico PL, Bonini S. Age-related ocular surface failure: A narrative review. Exp Eye Res 2022; 219:109035. [DOI: 10.1016/j.exer.2022.109035] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 02/28/2022] [Accepted: 03/13/2022] [Indexed: 12/26/2022]
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Qi R, Qin W. Role of Complement System in Kidney Transplantation: Stepping From Animal Models to Clinical Application. Front Immunol 2022; 13:811696. [PMID: 35281019 PMCID: PMC8913494 DOI: 10.3389/fimmu.2022.811696] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 01/31/2022] [Indexed: 12/23/2022] Open
Abstract
Kidney transplantation is a life-saving strategy for patients with end-stage renal diseases. Despite the advances in surgical techniques and immunosuppressive agents, the long-term graft survival remains a challenge. Growing evidence has shown that the complement system, part of the innate immune response, is involved in kidney transplantation. Novel insights highlighted the role of the locally produced and intracellular complement components in the development of inflammation and the alloreactive response in the kidney allograft. In the current review, we provide the updated understanding of the complement system in kidney transplantation. We will discuss the involvement of the different complement components in kidney ischemia-reperfusion injury, delayed graft function, allograft rejection, and chronic allograft injury. We will also introduce the existing and upcoming attempts to improve allograft outcomes in animal models and in the clinical setting by targeting the complement system.
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Affiliation(s)
| | - Weijun Qin
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
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Weeks LD, Marinac CR, Redd R, Abel G, Lin A, Agrawal M, Stone RM, Schrag D, Ebert BL. Age-related diseases of inflammation in myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 2022; 139:1246-1250. [PMID: 34875037 PMCID: PMC8874362 DOI: 10.1182/blood.2021014418] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 11/30/2021] [Indexed: 01/07/2023] Open
Affiliation(s)
- Lachelle D Weeks
- Department of Medical Oncology
- Center for Prevention of Progression
| | - Catherine R Marinac
- Center for Prevention of Progression
- Division of Population Sciences, Department of Medical Oncology
- Department of Data Science, and
| | - Robert Redd
- Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA
| | - Gregory Abel
- Division of Population Sciences, Department of Medical Oncology
- Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA
| | - Amy Lin
- Center for Prevention of Progression
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA
| | | | - Richard M Stone
- Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA
| | - Deborah Schrag
- Division of Population Sciences, Department of Medical Oncology
| | - Benjamin L Ebert
- Department of Medical Oncology
- Center for Prevention of Progression
- Broad Institute, Massachusetts Institute of Technology and Harvard University, Cambridge, MA; and
- Howard Hughes Medical Institute, Boston, MA
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Fawzy MA, Maher SA, El-Rehany MA, Welson NN, Albezrah NKA, Batiha GES, Fathy M. Vincamine Modulates the Effect of Pantoprazole in Renal Ischemia/Reperfusion Injury by Attenuating MAPK and Apoptosis Signaling Pathways. Molecules 2022; 27:1383. [PMID: 35209172 PMCID: PMC8879001 DOI: 10.3390/molecules27041383] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 02/11/2022] [Accepted: 02/15/2022] [Indexed: 02/06/2023] Open
Abstract
Pantoprazole has an antioxidant function against reactive oxygen species (ROS). Vincamine, a herbal candidate, is an indole alkaloid of clinical use against brain sclerosis. The aim of the present experiment is to evaluate, on a molecular level for the first time, the value of vincamine in addition to pantoprazole in treating experimentally induced renal ischemia/reperfusion injury (IRI). One-hundred-and-twenty-eight healthy male Wistar albino rats were included. Serum creatinine, blood urea nitrogen, and malondialdehyde levels were assessed. ELISA was used to estimate the pro-inflammatory cytokines. The expression of Bcl-2 and Bax genes was assessed by quantitative real-time PCR. ERK1/2, JNK1/2, p38, cleaved caspase-3, and NF-κB proteins expressions were estimated using western blot assay. The kidneys were also histopathologically studied. The IRI resulted in impaired cellular functions with increased creatinine, urea nitrogen, malondialdehyde, TNF-α, IL-6, and IL-1β serum levels, and up-regulated NF-ĸB, JNK1/2, ERK1/2, p38, and cleaved caspase-3 proteins. Furthermore, it down-regulated the expression of the Bcl-2 gene and upregulated the Bax gene. The treatment with vincamine, in addition to pantoprazole multiple doses, significantly alleviated the biochemical and histopathological changes more than pantoprazole or vincamine alone, whether the dose is single or multiple, declaring their synergistic effect. In conclusion, vincamine with pantoprazole multiple doses mitigated the renal IRI through the inhibition of apoptosis, attenuation of the extracellular signaling pathways through proinflammatory cytokines' levels, and suppression of the MAPK (ERK1/2, JNK, p38)-NF-κB intracellular signaling pathway.
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Affiliation(s)
- Michael A. Fawzy
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt;
| | - Sherif A. Maher
- Department of Biochemistry, Faculty of Pharmacy, Deraya University, Minia 61111, Egypt; (S.A.M.); (M.A.E.-R.)
| | - Mahmoud A. El-Rehany
- Department of Biochemistry, Faculty of Pharmacy, Deraya University, Minia 61111, Egypt; (S.A.M.); (M.A.E.-R.)
| | - Nermeen N. Welson
- Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Beni-Suef University, Beni-Suef 62511, Egypt;
| | - Nisreen K. A. Albezrah
- Department of Obstetrics and Gynecology, College of Medicine, Taif University, Taif 21944, Saudi Arabia;
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour 22511, Egypt;
| | - Moustafa Fathy
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt;
- Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan
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Wang W, Sheng L, Chen Y, Li Z, Wu H, Ma J, Zhang D, Chen X, Zhang S. Total coumarin derivates from Hydrangea paniculata attenuate renal injuries in cationized-BSA induced membranous nephropathy by inhibiting complement activation and interleukin 10-mediated interstitial fibrosis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 96:153886. [PMID: 35026512 DOI: 10.1016/j.phymed.2021.153886] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 11/21/2021] [Accepted: 12/05/2021] [Indexed: 06/14/2023]
Abstract
BACKGROUND Total coumarins extracted from Hydrangea. Paniculata, Sieb (HP) have showed renal protective effect in several experimental acute and chronic kidney diseases. PURPOSE The aim of current study is to evaluate renal protective effect of HP against cationized-BSA (c-BSA) induced experimental membranous nephritis (MN), and further investigate its underlying mechanisms. METHODS Rat MN model was established by intravenous injection of 5 mg c-BSA for consecutive 14 days, and after albuminuria confirmed, HP was orally administrated with 7.5, 15, 30 mg/kg for nine weeks. The renal function was measured and histopathological injuries were observed. RNA sequencing was used to analyze the altered signaling pathways in kidneys. Pharmacokinetics was performed to investigate the pharmacodynamics of major ingredients in HP and possible metabolites. Discover X platform helped to clarify the possible molecular mechanisms of major compound in HP. RESULTS HP administration could significantly improve the renal function, and ameliorate the dyslipidemia and histopathological injuries. mRNA sequencing demonstrated that HP had anti-inflammation and anti-fibrosis effects possible through down-regulating the complement activation and PI3K-AKT pathways. Pharmacokinetics demonstrated that skimmin and 7-hydoxycoumarin (7-HC) were major compound or metabolite in plasma after oral administration. Based on Discover X platform, we confirmed that skimmin and 7-HC inhibited the IL10 production by inflammatory macrophages through blocking PI3K-AKT and NFκB signaling pathways. Finally, we demonstrated that HP protected tubulointerstitium from complement attack by reducing the C3 self-production and auto-cleavage in tubular cells. CONCLUSIONS HP has a renal protective effect, and its drug development may provide one alternative strategy to treat immune-mediated nephropathy.
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Affiliation(s)
- Weida Wang
- State key laboratory of bioactive substances and functions of natural medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union medical college, Beijing, 100050, P.R. China
| | - Li Sheng
- State key laboratory of bioactive substances and functions of natural medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union medical college, Beijing, 100050, P.R. China
| | - Yuanyuan Chen
- State key laboratory of bioactive substances and functions of natural medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union medical college, Beijing, 100050, P.R. China
| | - Zhaojun Li
- State key laboratory of bioactive substances and functions of natural medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union medical college, Beijing, 100050, P.R. China
| | - Haijie Wu
- State key laboratory of bioactive substances and functions of natural medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union medical college, Beijing, 100050, P.R. China
| | - Jie Ma
- State key laboratory of bioactive substances and functions of natural medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union medical college, Beijing, 100050, P.R. China
| | - Dongming Zhang
- State key laboratory of bioactive substances and functions of natural medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union medical college, Beijing, 100050, P.R. China
| | - Xiaoguang Chen
- State key laboratory of bioactive substances and functions of natural medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union medical college, Beijing, 100050, P.R. China.
| | - Sen Zhang
- State key laboratory of bioactive substances and functions of natural medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union medical college, Beijing, 100050, P.R. China.
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Molema G, Zijlstra JG, van Meurs M, Kamps JAAM. Renal microvascular endothelial cell responses in sepsis-induced acute kidney injury. Nat Rev Nephrol 2022; 18:95-112. [PMID: 34667283 DOI: 10.1038/s41581-021-00489-1] [Citation(s) in RCA: 78] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/10/2021] [Indexed: 12/29/2022]
Abstract
Microvascular endothelial cells in the kidney have been a neglected cell type in sepsis-induced acute kidney injury (sepsis-AKI) research; yet, they offer tremendous potential as pharmacological targets. As endothelial cells in distinct cortical microvascular segments are highly heterogeneous, this Review focuses on endothelial cells in their anatomical niche. In animal models of sepsis-AKI, reduced glomerular blood flow has been attributed to inhibition of endothelial nitric oxide synthase activation in arterioles and glomeruli, whereas decreased cortex peritubular capillary perfusion is associated with epithelial redox stress. Elevated systemic levels of vascular endothelial growth factor, reduced levels of circulating sphingosine 1-phosphate and loss of components of the glycocalyx from glomerular endothelial cells lead to increased microvascular permeability. Although coagulation disbalance occurs in all microvascular segments, the molecules involved differ between segments. Induction of the expression of adhesion molecules and leukocyte recruitment also occurs in a heterogeneous manner. Evidence of similar endothelial cell responses has been found in kidney and blood samples from patients with sepsis. Comprehensive studies are needed to investigate the relationships between segment-specific changes in the microvasculature and kidney function loss in sepsis-AKI. The application of omics technologies to kidney tissues from animals and patients will be key in identifying these relationships and in developing novel therapeutics for sepsis.
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Affiliation(s)
- Grietje Molema
- Dept. Pathology and Medical Biology, Medical Biology section, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
| | - Jan G Zijlstra
- Dept. Critical Care, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Matijs van Meurs
- Dept. Pathology and Medical Biology, Medical Biology section, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.,Dept. Critical Care, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Jan A A M Kamps
- Dept. Pathology and Medical Biology, Medical Biology section, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
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Abstract
Acute kidney injury (AKI) is a common clinical complication characterized by a sudden deterioration of the kidney's excretory function, which normally occurs secondary to another serious illness. AKI is an important risk factor for chronic kidney disease (CKD) occurrence and progression to kidney failure. It is, therefore, crucial to block the development of AKI as early as possible. To date, existing animal studies have shown that senescence occurs in the early stage of AKI and is extremely critical to prognosis. Cellular senescence is an irreversible process of cell cycle arrest that is accompanied by alterations at the transcriptional, metabolic, and secretory levels along with modified cellular morphology and chromatin organization. Acute cellular senescence tends to play an active role, whereas chronic senescence plays a dominant role in the progression of AKI to CKD. The occurrence of chronic senescence is inseparable from senescence-associated secretory phenotype (SASP) and senescence-related pathways. SASP acts on normal cells to amplify the senescence signal through senescence-related pathways. Senescence can be improved by initiating reprogramming, which plays a crucial role in blocking the progression of AKI to CKD. This review integrates the existing studies on senescence in AKI from several aspects to find meaningful research directions to improve the prognosis of AKI and prevent the progression of CKD.
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37
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Picerno A, Stasi A, Franzin R, Curci C, di Bari I, Gesualdo L, Sallustio F. Why stem/progenitor cells lose their regenerative potential. World J Stem Cells 2021; 13:1714-1732. [PMID: 34909119 PMCID: PMC8641024 DOI: 10.4252/wjsc.v13.i11.1714] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 05/26/2021] [Accepted: 10/31/2021] [Indexed: 02/06/2023] Open
Abstract
Nowadays, it is clear that adult stem cells, also called as tissue stem cells, play a central role to repair and maintain the tissue in which they reside by their self-renewal ability and capacity of differentiating into distinct and specialized cells. As stem cells age, their renewal ability declines and their capacity to maintain organ homeostasis and regeneration is impaired. From a molecular perspective, these changes in stem cells properties can be due to several types of cell intrinsic injury and DNA aberrant alteration (i.e epigenomic profile) as well as changes in the tissue microenviroment, both into the niche and by systemic circulating factors. Strikingly, it has been suggested that aging-induced deterioration of stem cell functions may play a key role in the pathophysiology of the various aging-associated disorders. Therefore, understanding how resident stem cell age and affects near and distant tissues is fundamental. Here, we examine the current knowledge about aging mechanisms in several kinds of adult stem cells under physiological and pathological conditions and the principal aging-related changes in number, function and phenotype that determine the loss of tissue renewal properties. Furthermore, we examine the possible cell rejuvenation strategies. Stem cell rejuvenation may reverse the aging phenotype and the discovery of effective methods for inducing and differentiating pluripotent stem cells for cell replacement therapies could open up new possibilities for treating age-related diseases.
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Affiliation(s)
- Angela Picerno
- Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Bari 70124, Italy
| | - Alessandra Stasi
- Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Bari 70124, Italy
| | - Rossana Franzin
- Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Bari 70124, Italy
| | - Claudia Curci
- Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Bari 70124, Italy
| | - Ighli di Bari
- Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Bari 70124, Italy
| | - Loreto Gesualdo
- Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Bari 70124, Italy
| | - Fabio Sallustio
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Bari 70124, Italy
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Abstract
Elderly individuals with chronic disorders tend to develop inflammaging, a condition associated with elevated levels of blood inflammatory markers, and increased susceptibility to chronic disease progression. Native and adaptive immunity are both involved in immune system senescence, kidney fibrosis and aging. The innate immune system is characterized by a limited number of receptors, constantly challenged by self and non-self stimuli. Circulating and kidney resident myeloid and lymphoid cells are all equipped with pattern recognition receptors (PRRs). Recent reports on PRRs show kidney overexpression of toll-like receptors (TLRs) in inflammaging autoimmune renal diseases, vasculitis, acute kidney injury and kidney transplant rejection. TLR upregulation leads to proinflammatory cytokine induction, fibrosis, and chronic kidney disease progression. TLR2 blockade in a murine model of renal ischemia reperfusion injury prevented the escape of natural killer cells and neutrophils by inflammaging kidney injury. Tumor necrosis factor-α blockade in endothelial cells with senescence-associated secretory phenotype significantly reduced interleukin-6 release. These findings should encourage experimental and translational clinical trials aimed at modulating renal inflammaging by native immunity blockade.
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Ueda S, Tominaga T, Ochi A, Sakurai A, Nishimura K, Shibata E, Wakino S, Tamaki M, Nagai K. TGF-β1 is involved in senescence-related pathways in glomerular endothelial cells via p16 translocation and p21 induction. Sci Rep 2021; 11:21643. [PMID: 34737348 PMCID: PMC8569175 DOI: 10.1038/s41598-021-01150-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 10/25/2021] [Indexed: 12/18/2022] Open
Abstract
p16 inhibits cyclin-dependent kinases and regulates senescence-mediated arrest as well as p21. Nuclear p16 promotes G1 cell cycle arrest and cellular senescence. In various glomerular diseases, nuclear p16 expression is associated with disease progression. Therefore, the location of p16 is important. However, the mechanism of p16 trafficking between the nucleus and cytoplasm is yet to be fully investigated. TGF-β1, a major cytokine involved in the development of kidney diseases, can upregulate p21 expression. However, the relationship between TGF-β1 and p16 is poorly understood. Here, we report the role of podocyte TGF-β1 in regulating the p16 behavior in glomerular endothelial cells. We analyzed podocyte-specific TGF-β1 overexpression mice. Although p16 was found in the nuclei of glomerular endothelial cells and led to endothelial cellular senescence, the expression of p16 did not increase in glomeruli. In cultured endothelial cells, TGF-β1 induced nuclear translocation of p16 without increasing its expression. Among human glomerular diseases, p16 was detected in the nuclei of glomerular endothelial cells. In summary, we demonstrated the novel role of podocyte TGF-β1 in managing p16 behavior and cellular senescence in glomeruli, which has clinical relevance for the progression of human glomerular diseases.
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Affiliation(s)
- Sayo Ueda
- Department of Nephrology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15, Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Tatsuya Tominaga
- Department of Nephrology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15, Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Arisa Ochi
- Department of Nephrology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15, Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Akiko Sakurai
- Department of Nephrology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15, Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Kenji Nishimura
- Department of Nephrology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15, Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Eriko Shibata
- Department of Nephrology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15, Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Shu Wakino
- Department of Nephrology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15, Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Masanori Tamaki
- Department of Nephrology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15, Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Kojiro Nagai
- Department of Nephrology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15, Kuramoto-cho, Tokushima, 770-8503, Japan.
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Fawzy MA, Maher SA, Bakkar SM, El-Rehany MA, Fathy M. Pantoprazole Attenuates MAPK (ERK1/2, JNK, p38)-NF-κB and Apoptosis Signaling Pathways after Renal Ischemia/Reperfusion Injury in Rats. Int J Mol Sci 2021; 22:ijms221910669. [PMID: 34639009 PMCID: PMC8508698 DOI: 10.3390/ijms221910669] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 09/23/2021] [Accepted: 09/28/2021] [Indexed: 01/01/2023] Open
Abstract
Ischemia/reperfusion injury (IRI) in the kidney is the most common cause of acute renal dysfunction through different cell damage mechanisms. This study aimed to investigate, on molecular basics for the first time, the effect of pantoprazole on renal IRI in rats. Different biochemical parameters and oxidative stress markers were assessed. ELISA was used to estimate proinflammatory cytokines. qRT-PCR and western blot were used to investigate the gene and protein expression. Renal histopathological examination was also performed. IRI resulted in tissue damage, elevation of serum levels of creatinine, urea nitrogen, malondialdehyde, TNF-α, IL-6, IL-1β, up-regulation of NF-κB, JNK1/2, ERK1/2, p38, and cleaved caspase-3 proteins. Furthermore, it up-regulated the expression of the Bax gene and down-regulated the expression of the Bcl-2 gene. Treatment of the injured rats with pantoprazole, either single dose or multiple doses, significantly alleviated IRI-induced biochemical and histopathological changes, attenuated the levels of proinflammatory cytokines, down-regulated the expression of NF-κB, JNK1/2, ERK1/2, p38, and cleaved caspase-3 proteins, and the Bax gene, and up-regulated Bcl-2 gene expression. Moreover, treatment with pantoprazole multiple doses has an ameliorative effect that is greater than pantoprazole single-dose. In conclusion, pantoprazole diminished renal IRI via suppression of apoptosis, attenuation of the pro-inflammatory cytokines’ levels, and inhibition of the intracellular signaling pathway MAPK (ERK1/2, JNK, p38)–NF-κB.
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Affiliation(s)
- Michael A. Fawzy
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt;
| | - Sherif A. Maher
- Department of Biochemistry, Faculty of Pharmacy, Deraya University, Minia 61111, Egypt; (S.A.M.); (M.A.E.-R.)
| | - Sally M. Bakkar
- Department of Biochemistry, Faculty of Medicine, Assiut University, Assiut 71515, Egypt;
| | - Mahmoud A. El-Rehany
- Department of Biochemistry, Faculty of Pharmacy, Deraya University, Minia 61111, Egypt; (S.A.M.); (M.A.E.-R.)
| | - Moustafa Fathy
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt;
- Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan
- Correspondence: or
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Netti GS, Franzin R, Stasi A, Spadaccino F, Dello Strologo A, Infante B, Gesualdo L, Castellano G, Ranieri E, Stallone G. Role of Complement in Regulating Inflammation Processes in Renal and Prostate Cancers. Cells 2021; 10:cells10092426. [PMID: 34572075 PMCID: PMC8471315 DOI: 10.3390/cells10092426] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Revised: 09/06/2021] [Accepted: 09/08/2021] [Indexed: 01/10/2023] Open
Abstract
For decades, the complement system, the central pillar of innate immune response, was recognized as a protective mechanism against cancer cells and the manipulation of complement effector functions in cancer setting offered a great opportunity to improve monoclonal antibody-based cancer immunotherapies. Similarly, cellular senescence, the process of cell cycle arrest that allow DNA and tissue repair has been traditionally thought to be able to suppress tumor progression. However, in recent years, extensive research has identified the complement system and cellular senescence as two main inducers of tumour growth in the context of chronic, persistent inflammation named inflammaging. Here, we discuss the data describing the ambivalent role of senescence in cancer with a particular focus on tumors that are strongly dependent on complement activation and can be understood by a new, senescence-related point of view: prostate cancer and renal cell carcinoma.
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Affiliation(s)
- Giuseppe Stefano Netti
- Clinical Pathology, Center of Molecular Medicine, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (G.S.N.); (F.S.)
| | - Rossana Franzin
- Department of Emergency and Organ Transplantation-Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, 70124 Bari, Italy; (R.F.); (A.S.); (L.G.)
| | - Alessandra Stasi
- Department of Emergency and Organ Transplantation-Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, 70124 Bari, Italy; (R.F.); (A.S.); (L.G.)
| | - Federica Spadaccino
- Clinical Pathology, Center of Molecular Medicine, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (G.S.N.); (F.S.)
| | - Andrea Dello Strologo
- Department of Medical and Surgical Sciences-Nephrology, Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), University of Foggia, 71122 Foggia, Italy; (A.D.S.); (B.I.); (G.C.)
| | - Barbara Infante
- Department of Medical and Surgical Sciences-Nephrology, Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), University of Foggia, 71122 Foggia, Italy; (A.D.S.); (B.I.); (G.C.)
| | - Loreto Gesualdo
- Department of Emergency and Organ Transplantation-Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, 70124 Bari, Italy; (R.F.); (A.S.); (L.G.)
| | - Giuseppe Castellano
- Department of Medical and Surgical Sciences-Nephrology, Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), University of Foggia, 71122 Foggia, Italy; (A.D.S.); (B.I.); (G.C.)
| | - Elena Ranieri
- Clinical Pathology, Center of Molecular Medicine, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (G.S.N.); (F.S.)
- Correspondence: (E.R.); (G.S.); Tel.: +39-0881-732611 (E.R.); +39-0881-736002 (G.S.)
| | - Giovanni Stallone
- Department of Medical and Surgical Sciences-Nephrology, Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), University of Foggia, 71122 Foggia, Italy; (A.D.S.); (B.I.); (G.C.)
- Correspondence: (E.R.); (G.S.); Tel.: +39-0881-732611 (E.R.); +39-0881-736002 (G.S.)
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42
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Franzin R, Stasi A, Fiorentino M, Simone S, Oberbauer R, Castellano G, Gesualdo L. Renal Delivery of Pharmacologic Agents During Machine Perfusion to Prevent Ischaemia-Reperfusion Injury: From Murine Model to Clinical Trials. Front Immunol 2021; 12:673562. [PMID: 34295329 PMCID: PMC8290413 DOI: 10.3389/fimmu.2021.673562] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Accepted: 06/21/2021] [Indexed: 12/12/2022] Open
Abstract
Donor organ shortage still remains a serious obstacle for the access of wait-list patients to kidney transplantation, the best treatment for End-Stage Kidney Disease (ESKD). To expand the number of transplants, the use of lower quality organs from older ECD or DCD donors has become an established routine but at the price of increased incidence of Primary Non-Function, Delay Graft Function and lower-long term graft survival. In the last years, several improvements have been made in the field of renal transplantation from surgical procedure to preservation strategies. To improve renal outcomes, research has focused on development of innovative and dynamic preservation techniques, in order to assess graft function and promote regeneration by pharmacological intervention before transplantation. This review provides an overview of the current knowledge of these new preservation strategies by machine perfusions and pharmacological interventions at different timing possibilities: in the organ donor, ex-vivo during perfusion machine reconditioning or after implementation in the recipient. We will report therapies as anti-oxidant and anti-inflammatory agents, senolytics agents, complement inhibitors, HDL, siRNA and H2S supplementation. Renal delivery of pharmacologic agents during preservation state provides a window of opportunity to treat the organ in an isolated manner and a crucial route of administration. Even if few studies have been reported of transplantation after ex-vivo drugs administration, targeting the biological pathway associated to kidney failure (i.e. oxidative stress, complement system, fibrosis) might be a promising therapeutic strategy to improve the quality of various donor organs and expand organ availability.
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Affiliation(s)
- Rossana Franzin
- Department of Emergency and Organ Transplantation, Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari, Italy
| | - Alessandra Stasi
- Department of Emergency and Organ Transplantation, Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari, Italy
| | - Marco Fiorentino
- Department of Emergency and Organ Transplantation, Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari, Italy
| | - Simona Simone
- Department of Emergency and Organ Transplantation, Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari, Italy
| | - Rainer Oberbauer
- Department of Nephrology and Dialysis, University Clinic for Internal Medicine III, Medical University Vienna, Vienna, Austria
| | - Giuseppe Castellano
- Nephrology, Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Loreto Gesualdo
- Department of Emergency and Organ Transplantation, Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari, Italy
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Mezzolla V, Pontrelli P, Fiorentino M, Stasi A, Pesce F, Franzin R, Rascio F, Grandaliano G, Stallone G, Infante B, Gesualdo L, Castellano G. Emerging biomarkers of delayed graft function in kidney transplantation. Transplant Rev (Orlando) 2021; 35:100629. [PMID: 34118742 DOI: 10.1016/j.trre.2021.100629] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 05/10/2021] [Accepted: 05/24/2021] [Indexed: 01/10/2023]
Abstract
Delayed Graft Function (DGF) is one of the most common early complications in kidney transplantation, associated with poor graft outcomes, prolonged post-operative hospitalization and higher rejection rates. Given the severe shortage of high-quality organs for transplantation, DGF incidence is expected to raise in the next years because of the use of nonstandard kidneys from Extended Criteria Donors (ECD) and from Donors after Circulatory Death (DCD). Alongside conventional methods for the evaluation of renal allograft [e.g. serum creatinine Glomerular Filtration Rate (GFR), needle biopsy], recent advancements in omics technologies, including proteomics, metabolomics and transcriptomics, may allow to discover novel biomarkers associated with DGF occurrence, in order to identify early preclinical signs of renal dysfunction and to improve the quality of graft management. Here, we gather contributions from basic scientists and clinical researchers to describe new omics studies in renal transplantation, reporting the emerging biomarkers of DGF that may implement and improve conventional approaches.
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Affiliation(s)
- Valeria Mezzolla
- Department of Emergency and Organ Transplantation, Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari 70124, Italy
| | - Paola Pontrelli
- Department of Emergency and Organ Transplantation, Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari 70124, Italy
| | - Marco Fiorentino
- Department of Emergency and Organ Transplantation, Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari 70124, Italy
| | - Alessandra Stasi
- Department of Emergency and Organ Transplantation, Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari 70124, Italy
| | - Francesco Pesce
- Department of Emergency and Organ Transplantation, Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari 70124, Italy
| | - Rossana Franzin
- Department of Emergency and Organ Transplantation, Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari 70124, Italy
| | - Federica Rascio
- Department of Emergency and Organ Transplantation, Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari 70124, Italy
| | - Giuseppe Grandaliano
- Department of Translational Medicine and Surgery, Università Cattolica Sacro Cuore, Rome, Italy
| | - Giovanni Stallone
- Nephrology, Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, Italy
| | - Barbara Infante
- Nephrology, Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, Italy
| | - Loreto Gesualdo
- Department of Emergency and Organ Transplantation, Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari 70124, Italy
| | - Giuseppe Castellano
- Nephrology, Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, Italy.
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Kielar M, Gala-Błądzińska A, Dumnicka P, Ceranowicz P, Kapusta M, Naumnik B, Kubiak G, Kuźniewski M, Kuśnierz-Cabala B. Complement Components in the Diagnosis and Treatment after Kidney Transplantation-Is There a Missing Link? Biomolecules 2021; 11:biom11060773. [PMID: 34064132 PMCID: PMC8224281 DOI: 10.3390/biom11060773] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 05/14/2021] [Accepted: 05/18/2021] [Indexed: 12/25/2022] Open
Abstract
Currently, kidney transplantation is widely accepted as the renal replacement therapy allowing for the best quality of life and longest survival of patients developing end-stage renal disease. However, chronic transplant rejection, recurrence of previous kidney disease or newly acquired conditions, or immunosuppressive drug toxicity often lead to a deterioration of kidney allograft function over time. Complement components play an important role in the pathogenesis of kidney allograft impairment. Most studies on the role of complement in kidney graft function focus on humoral rejection; however, complement has also been associated with cell mediated rejection, post-transplant thrombotic microangiopathy, the recurrence of several glomerulopathies in the transplanted kidney, and transplant tolerance. Better understanding of the complement involvement in the transplanted kidney damage has led to the development of novel therapies that inhibit complement components and improve graft survival. The analysis of functional complotypes, based on the genotype of both graft recipient and donor, may become a valuable tool for assessing the risk of acute transplant rejection. The review summarizes current knowledge on the pathomechanisms of complement activation following kidney transplantation and the resulting diagnostic and therapeutic possibilities.
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Affiliation(s)
- Małgorzata Kielar
- St. Louis Regional Children’s Hospital, Medical Diagnostic Laboratory with a Bacteriology Laboratory, Strzelecka 2 St., 31-503 Kraków, Poland;
| | - Agnieszka Gala-Błądzińska
- Medical College of Rzeszów University, Institute of Medical Sciences, Kopisto 2A Avn., 35-310 Rzeszów, Poland;
| | - Paulina Dumnicka
- Jagiellonian University Medical College, Faculty of Pharmacy, Department of Medical Diagnostics, Medyczna 9 St., 30-688 Kraków, Poland;
| | - Piotr Ceranowicz
- Jagiellonian University Medical College, Faculty of Medicine, Department of Physiology, Grzegórzecka 16 St., 31-531 Kraków, Poland;
| | - Maria Kapusta
- Jagiellonian University Medical College, Faculty of Medicine, Chair of Clinical Biochemistry, Department of Diagnostics, Kopernika 15A St., 31-501 Kraków, Poland;
| | - Beata Naumnik
- Medical University of Białystok, Faculty of Medicine, 1st Department of Nephrology and Transplantation with Dialysis Unit, Żurawia 14 St., 15-540 Białystok, Poland;
| | - Grzegorz Kubiak
- Catholic University of Leuven, Department of Cardiovascular Diseases, 3000 Leuven, Belgium;
| | - Marek Kuźniewski
- Jagiellonian University Medical College, Faculty of Medicine, Chair and Department of Nephrology, Jakubowskiego 2 St., 30-688 Kraków, Poland;
| | - Beata Kuśnierz-Cabala
- Jagiellonian University Medical College, Faculty of Medicine, Chair of Clinical Biochemistry, Department of Diagnostics, Kopernika 15A St., 31-501 Kraków, Poland;
- Correspondence: ; Tel.: +48-12-424-83-65
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Franzin R, Stasi A, Ranieri E, Netti GS, Cantaluppi V, Gesualdo L, Stallone G, Castellano G. Targeting Premature Renal Aging: from Molecular Mechanisms of Cellular Senescence to Senolytic Trials. Front Pharmacol 2021; 12:630419. [PMID: 33995028 PMCID: PMC8117359 DOI: 10.3389/fphar.2021.630419] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 03/11/2021] [Indexed: 01/10/2023] Open
Abstract
The biological process of renal aging is characterized by progressive structural and functional deterioration of the kidney leading to end-stage renal disease, requiring renal replacement therapy. Since the discovery of pivotal mechanisms of senescence such as cell cycle arrest, apoptosis inhibition, and the development of a senescence-associated secretory phenotype (SASP), efforts in the understanding of how senescent cells participate in renal physiological and pathological aging have grown exponentially. This has been encouraged by both preclinical studies in animal models with senescent cell clearance or genetic depletion as well as due to evidence coming from the clinical oncologic experience. This review considers the molecular mechanism and pathways that trigger premature renal aging from mitochondrial dysfunction, epigenetic modifications to autophagy, DNA damage repair (DDR), and the involvement of extracellular vesicles. We also discuss the different pharmaceutical approaches to selectively target senescent cells (namely, senolytics) or the development of systemic SASP (called senomorphics) in basic models of CKD and clinical trials. Finally, an overview will be provided on the potential opportunities for their use in renal transplantation during ex vivo machine perfusion to improve the quality of the graft.
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Affiliation(s)
- Rossana Franzin
- Department of Emergency and Organ Transplantation, Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari, Italy
| | - Alessandra Stasi
- Department of Emergency and Organ Transplantation, Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari, Italy
| | - Elena Ranieri
- Clinical Pathology, Center of Molecular Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Giuseppe Stefano Netti
- Clinical Pathology, Center of Molecular Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Vincenzo Cantaluppi
- Nephrology and Kidney Transplantation Unit, Department of Translational Medicine and Center for Autoimmune and Allergic Diseases (CAAD), University of Piemonte Orientale (UPO), Novara, Italy
| | - Loreto Gesualdo
- Department of Emergency and Organ Transplantation, Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari, Italy
| | - Giovanni Stallone
- Nephrology, Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, Italy
| | - Giuseppe Castellano
- Nephrology, Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, Italy
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Divella C, Stasi A, Franzin R, Rossini M, Pontrelli P, Sallustio F, Netti GS, Ranieri E, Lacitignola L, Staffieri F, Crovace AM, Lucarelli G, Ditonno P, Battaglia M, Daha MR, van der Pol P, van Kooten C, Grandaliano G, Gesualdo L, Stallone G, Castellano G. Pentraxin-3-mediated complement activation in a swine model of renal ischemia/reperfusion injury. Aging (Albany NY) 2021; 13:10920-10933. [PMID: 33875620 PMCID: PMC8109140 DOI: 10.18632/aging.202992] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Accepted: 03/26/2021] [Indexed: 11/30/2022]
Abstract
Pentraxins are a family of evolutionarily conserved pattern recognition molecules with pivotal roles in innate immunity and inflammation, such as opsonization of pathogens during bacterial and viral infections. In particular, the long Pentraxin 3 (PTX3) has been shown to regulate several aspects of vascular and tissue inflammation during solid organ transplantation. Our study investigated the role of PTX3 as possible modulator of Complement activation in a swine model of renal ischemia/reperfusion (I/R) injury. We demonstrated that I/R injury induced early PTX3 deposits at peritubular and glomerular capillary levels. Confocal laser scanning microscopy revealed PTX3 deposits co-localizing with CD31+ endothelial cells. In addition, PTX3 was associated with infiltrating macrophages (CD163), dendritic cells (SWC3a) and myofibroblasts (FSP1). In particular, we demonstrated a significant PTX3-mediated activation of classical (C1q-mediated) and lectin (MBL-mediated) pathways of Complement. Interestingly, PTX3 deposits co-localized with activation of the terminal Complement complex (C5b-9) on endothelial cells, indicating that PTX3-mediated Complement activation occurred mainly at the renal vascular level. In conclusion, these data indicate that PTX3 might be a potential therapeutic target to prevent Complement-induced I/R injury.
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Affiliation(s)
- Chiara Divella
- Renal, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| | - Alessandra Stasi
- Renal, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| | - Rossana Franzin
- Renal, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| | - Michele Rossini
- Renal, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| | - Paola Pontrelli
- Renal, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| | - Fabio Sallustio
- Department of Interdisciplinary Medicine, University of Bari, Bari, Italy.,Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, Bari, Italy
| | - Giuseppe Stefano Netti
- Clinical Pathology Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Elena Ranieri
- Clinical Pathology Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Luca Lacitignola
- Veterinary Surgery Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| | - Francesco Staffieri
- Veterinary Surgery Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| | - Alberto Maria Crovace
- Veterinary Surgery Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| | - Giuseppe Lucarelli
- Urology, Andrology and Renal Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| | - Pasquale Ditonno
- Urology, Andrology and Renal Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| | - Michele Battaglia
- Urology, Andrology and Renal Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| | - Mohamed R Daha
- Department of Nephrology, University of Leiden, Leiden, The Netherlands
| | - Peter van der Pol
- Department of Nephrology, University of Leiden, Leiden, The Netherlands
| | - Cees van Kooten
- Department of Nephrology, University of Leiden, Leiden, The Netherlands
| | | | - Loreto Gesualdo
- Renal, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| | - Giovanni Stallone
- Nephrology, Dialysis and Transplantation Unit, Advanced Research center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Science, University of Foggia, Foggia, Italy
| | - Giuseppe Castellano
- Nephrology, Dialysis and Transplantation Unit, Advanced Research center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Science, University of Foggia, Foggia, Italy
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Palmisano A, Gandolfini I, Delsante M, Cantarelli C, Fiaccadori E, Cravedi P, Maggiore U. Acute Kidney Injury (AKI) before and after Kidney Transplantation: Causes, Medical Approach, and Implications for the Long-Term Outcomes. J Clin Med 2021; 10:1484. [PMID: 33918444 PMCID: PMC8038198 DOI: 10.3390/jcm10071484] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 03/28/2021] [Accepted: 03/29/2021] [Indexed: 12/14/2022] Open
Abstract
Acute kidney injury (AKI) is a common finding in kidney donors and recipients. AKI in kidney donor, which increases the risk of delayed graft function (DGF), may not by itself jeopardize the short- and long-term outcome of transplantation. However, some forms of AKI may induce graft rejection, fibrosis, and eventually graft dysfunction. Therefore, various strategies have been proposed to identify conditions at highest risk of AKI-induced DGF, that can be treated by targeting the donor, the recipient, or even the graft itself with the use of perfusion machines. AKI that occurs early post-transplant after a period of initial recovery of graft function may reflect serious and often occult systemic complications that may require prompt intervention to prevent graft loss. AKI that develops long after transplantation is often related to nephrotoxic drug reactions. In symptomatic patients, AKI is usually associated with various systemic medical complications and could represent a risk of mortality. Electronic systems have been developed to alert transplant physicians that AKI has occurred in a transplant recipient during long-term outpatient follow-up. Herein, we will review most recent understandings of pathophysiology, diagnosis, therapeutic approach, and short- and long-term consequences of AKI occurring in both the donor and in the kidney transplant recipient.
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Affiliation(s)
- Alessandra Palmisano
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (I.G.); (M.D.); (C.C.); (E.F.); (U.M.)
| | - Ilaria Gandolfini
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (I.G.); (M.D.); (C.C.); (E.F.); (U.M.)
- Nephrology Unit, Parma University Hospital, 43126 Parma, Italy
| | - Marco Delsante
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (I.G.); (M.D.); (C.C.); (E.F.); (U.M.)
- Nephrology Unit, Parma University Hospital, 43126 Parma, Italy
| | - Chiara Cantarelli
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (I.G.); (M.D.); (C.C.); (E.F.); (U.M.)
| | - Enrico Fiaccadori
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (I.G.); (M.D.); (C.C.); (E.F.); (U.M.)
- Nephrology Unit, Parma University Hospital, 43126 Parma, Italy
| | - Paolo Cravedi
- Renal Division, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;
| | - Umberto Maggiore
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (I.G.); (M.D.); (C.C.); (E.F.); (U.M.)
- Nephrology Unit, Parma University Hospital, 43126 Parma, Italy
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Galletti JG, de Paiva CS. The ocular surface immune system through the eyes of aging. Ocul Surf 2021; 20:139-162. [PMID: 33621658 PMCID: PMC8113112 DOI: 10.1016/j.jtos.2021.02.007] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 02/04/2021] [Accepted: 02/16/2021] [Indexed: 02/06/2023]
Abstract
Since the last century, advances in healthcare, housing, and education have led to an increase in life expectancy. Longevity is accompanied by a higher prevalence of age-related diseases, such as cancer, autoimmunity, diabetes, and infection, and part of this increase in disease incidence relates to the significant changes that aging brings about in the immune system. The eye is not spared by aging either, presenting with age-related disorders of its own, and interestingly, many of these diseases have immune pathophysiology. Being delicate organs that must be exposed to the environment in order to capture light, the eyes are endowed with a mucosal environment that protects them, the so-called ocular surface. As in other mucosal sites, immune responses at the ocular surface need to be swift and potent to eliminate threats but are at the same time tightly controlled to prevent excessive inflammation and bystander damage. This review will detail how aging affects the mucosal immune response of the ocular surface as a whole and how this process relates to the higher incidence of ocular surface disease in the elderly.
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Affiliation(s)
- Jeremias G Galletti
- Innate Immunity Laboratory, Institute of Experimental Medicine (IMEX), CONICET-National Academy of Medicine, Buenos Aires, Argentina.
| | - Cintia S de Paiva
- Ocular Surface Center, Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, 77030, USA.
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Cao JY, Ling LL, Ni WJ, Guo HL, Yang M. Autophagosome protects proximal tubular cells from aldosterone-induced senescence through improving oxidative stress. Ren Fail 2021; 43:556-565. [PMID: 33757397 PMCID: PMC7993373 DOI: 10.1080/0886022x.2021.1902821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Aldosterone exerts an enormous function on proximal tubular cells (PTC) senescence, which is a common pathomechanism contributing to renal dysfunction. Numerous studies have shown that oxidative stress is deeply involved in the pathophysiologic processes of chronic kidney diseases. The study aims to investigate whether autophagy could regulate the process of senescence through oxidative stress in PTC both in vivo and ex vivo. Our results suggested that aldosterone treatment increased the senescence and oxidative stress as evidenced by increased percent of SA-β-Gal positive cells, reactive oxygen species level, expression of NADPH oxidase 4 (NOX4) rather than NOX2, and the up-regulation of p21 in cultured PTC. Furthermore, the alternation of the expression of p62 and LC3-II/LC3-I demonstrated that aldosterone treatment remarkably influenced autophagic flux. NOX4 siRNA treatment or autophagy induction with rapamycin reduced the oxidative stress and senescence in aldosterone-induced PTC. On the contrary, inhibition of autophagy with chloroquine worsened these changes. Similar results were further confirmed in vivo. Our results suggested that autophagy may become a realistic therapeutic strategy against aldosterone-induced PTC injury via improving oxidative stress.
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Affiliation(s)
- Jing-Yuan Cao
- Department of Nephrology, Taizhou People's Hospital, The Fifth Affiliated Hospital of Nantong University, Taizhou, China
| | - Li-Lu Ling
- Department of Nephrology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Wei-Jie Ni
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China
| | - Hong-Lei Guo
- Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Min Yang
- Department of Nephrology, The Third Affiliated Hospital of Soochow University, Changzhou, China
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50
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Infante B, Bellanti F, Correale M, Pontrelli P, Franzin R, Leo S, Calvaruso M, Mercuri S, Netti GS, Ranieri E, Brunetti ND, Grandaliano G, Gesualdo L, Serviddio G, Castellano G, Stallone G. mTOR inhibition improves mitochondria function/biogenesis and delays cardiovascular aging in kidney transplant recipients with chronic graft dysfunction. Aging (Albany NY) 2021; 13:8026-8039. [PMID: 33758105 PMCID: PMC8034974 DOI: 10.18632/aging.202863] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 03/03/2021] [Indexed: 02/05/2023]
Abstract
CVD remains the major cause of mortality with graft functioning in Kidney transplant recipients (KTRs), with an estimated risk of CV events about 50-fold higher than in the general population. Many strategies have been considered to reduce the CV risk such as the use of mTOR inhibitors. We evaluate whether chronic mTOR inhibition might influence CV aging in KTRs studying the molecular mechanisms involved in this effect. We retrospectively analyzed 210 KTRs with stable graft function on therapy with CNI and mycophenolic acid (Group A, 105 pts.), or with CNI and mTORi (Everolimus, Group B, 105 pts.). The presence of mTOR inhibitor in immunosuppressive therapy was associated to increase serum levels of Klotho with concomitant reduction in FGF-23, with a significant decrease in left ventricular mass. In addition, KTRs with mTORi improved mitochondrial function/biogenesis in PBMC with more efficient oxidative phosphorylation, antioxidant capacity and glutathione peroxidase activity. Finally, group B KTRs presented reduced levels of inflammaging markers such as reduced serum pentraxin-3 and p21ink expression in PBMC. In conclusion, we demonstrated that mTOR inhibition in immunosuppressive protocols prevents the occurrence and signs of CV aging in KTRs.
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Affiliation(s)
- Barbara Infante
- Department of Medical and Surgical Sciences, Nephrology, Dialysis and Transplantation Unit, University of Foggia, Foggia, Italy
| | - Francesco Bellanti
- C.U.R.E. (University Center for Liver Disease Research and Treatment), Department of Medical and Surgical Sciences, University of Foggia, Italy
| | - Michele Correale
- Cardiology Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Paola Pontrelli
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Bari, Italy
| | - Rossana Franzin
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Bari, Italy
| | - Serena Leo
- Department of Medical and Surgical Sciences, Nephrology, Dialysis and Transplantation Unit, University of Foggia, Foggia, Italy
| | - Martina Calvaruso
- Department of Medical and Surgical Sciences, Nephrology, Dialysis and Transplantation Unit, University of Foggia, Foggia, Italy
| | - Silvia Mercuri
- Department of Medical and Surgical Sciences, Nephrology, Dialysis and Transplantation Unit, University of Foggia, Foggia, Italy
| | - Giuseppe Stefano Netti
- Department of Medical and Surgical Sciences, Nephrology, Dialysis and Transplantation Unit, University of Foggia, Foggia, Italy
| | - Elena Ranieri
- Clinical Pathology Unit and Center for Molecular Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Natale Daniele Brunetti
- Cardiology Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Giuseppe Grandaliano
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Università Cattolica del Sacro Cuore, Rome, Italy
| | - Loreto Gesualdo
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Bari, Italy
| | - Gaetano Serviddio
- C.U.R.E. (University Center for Liver Disease Research and Treatment), Department of Medical and Surgical Sciences, University of Foggia, Italy
| | - Giuseppe Castellano
- Department of Medical and Surgical Sciences, Nephrology, Dialysis and Transplantation Unit, University of Foggia, Foggia, Italy
| | - Giovanni Stallone
- Department of Medical and Surgical Sciences, Nephrology, Dialysis and Transplantation Unit, University of Foggia, Foggia, Italy
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