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Lv J, Lan B, Fu L, He C, Zhou W, Wang X, Zhou C, Mao Z, Chen Y, Mei C, Xue C. EZH2 inhibition or genetic ablation suppresses cyst growth in autosomal dominant polycystic kidney disease. J Transl Med 2024; 22:979. [PMID: 39472935 PMCID: PMC11520870 DOI: 10.1186/s12967-024-05785-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/07/2024] [Accepted: 10/18/2024] [Indexed: 11/02/2024] Open
Abstract
BACKGROUND Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a prevalent genetic disorder characterized by the formation of renal cysts leading to kidney failure. Despite known genetic underpinnings, the variability in disease progression suggests additional regulatory layers, including epigenetic modifications. METHODS We utilized various ADPKD models, including Pkd1 and Ezh2 conditional knockout (Pkd1delta/delta:Ezh2delta/delta) mice, to explore the role of Enhancer of Zeste Homolog 2 (EZH2) in cystogenesis. Pharmacological inhibition of EZH2 was performed using GSK126 or EPZ-6438 across multiple models. RESULTS EZH2 expression was significantly upregulated in Pkd1-/- cells, Pkd1delta/delta mice, and human ADPKD kidneys. EZH2 inhibition attenuates cyst development in MDCK cells and a mouse embryonic kidney cyst model. Both Ezh2 conditional knockout and GSK126 treatment suppressed renal cyst growth and protected renal function in Pkd1delta/delta mice. Mechanistically, cAMP/PKA/CREB pathway increased EZH2 expression. EZH2 mediated cystogenesis by enhancing methylation and activation of STAT3, promoting cell cycle through p21 suppression, and stimulating non-phosphorylated β-catenin in Wnt signaling pathway. Additionally, EZH2 enhanced ferroptosis by inhibiting SLC7A11 and GPX4 in ADPKD. CONCLUSION Our findings elucidate the pivotal role of EZH2 in promoting renal cyst growth through epigenetic mechanisms and suggest that EZH2 inhibition or ablation may serve as a novel therapeutic approach for managing ADPKD.
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Affiliation(s)
- Jiayi Lv
- Kidney Institute, Division of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University (Naval Medical University), 415 Fengyang Road, Shanghai, 200003, China
| | - Bingxue Lan
- Center for Clinical Laboratories, Affiliated Hospital of Guizhou Medical University, Guiyang City, Guizhou Province, China
- Department of Biochemistry and Molecular Biology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, 22 Qixiangtai Road, Tianjin, 300070, China
| | - Lili Fu
- Kidney Institute, Division of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University (Naval Medical University), 415 Fengyang Road, Shanghai, 200003, China
| | - Chaoran He
- Department of Biochemistry and Molecular Biology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, 22 Qixiangtai Road, Tianjin, 300070, China
| | - Wei Zhou
- Department of Nephrology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200080, China
| | - Xi Wang
- Institute of Infectious Diseases, Beijing Key Laboratory of Emerging Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China
- Beijing Institute of Infectious Diseases, Beijing, 100015, China
| | - Chenchen Zhou
- Outpatient Department, Yangpu Third Military Retreat, Shanghai, China
| | - Zhiguo Mao
- Kidney Institute, Division of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University (Naval Medical University), 415 Fengyang Road, Shanghai, 200003, China.
| | - Yupeng Chen
- Department of Biochemistry and Molecular Biology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, 22 Qixiangtai Road, Tianjin, 300070, China.
| | - Changlin Mei
- Kidney Institute, Division of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University (Naval Medical University), 415 Fengyang Road, Shanghai, 200003, China.
| | - Cheng Xue
- Kidney Institute, Division of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University (Naval Medical University), 415 Fengyang Road, Shanghai, 200003, China.
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Bin S, Yoo M, Molinari P, Gentile M, Budge K, Cantarelli C, Khan Y, La Manna G, Baldwin WM, Dvorina N, Cravedi P, Gusella GL. Reduced decay-accelerating factor expression promotes complement-mediated cystogenesis in murine ADPKD. JCI Insight 2024; 9:e175220. [PMID: 38912583 PMCID: PMC11383362 DOI: 10.1172/jci.insight.175220] [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] [Academic Contribution Register] [Received: 08/30/2023] [Accepted: 05/15/2024] [Indexed: 06/25/2024] Open
Abstract
Patients with autosomal dominant polycystic kidney disease (ADPKD), a genetic disease due to mutations of the PKD1 or PKD2 gene, show signs of complement activation in the urine and cystic fluid, but their pathogenic role in cystogenesis is unclear. We tested the causal relationship between complement activation and cyst growth using a Pkd1KO renal tubular cell line and newly generated conditional Pkd1-/- C3-/- mice. Pkd1-deficient tubular cells have increased expression of complement-related genes (C3, C5, CfB, C3ar, and C5ar1), while the gene and protein expression of complement regulators DAF, CD59, and Crry is decreased. Pkd1-/- C3-/- mice are unable to fully activate the complement cascade and are characterized by a significantly slower kidney cystogenesis, preserved renal function, and reduced intrarenal inflammation compared with Pkd1-/- C3+/+ controls. Transgenic expression of the cytoplasmic C-terminal tail of Pkd1 in Pkd1KO cells lowered C5ar1 expression, restored Daf levels, and reduced cell proliferation. Consistently, both DAF overexpression and pharmacological inhibition of C5aR1 (but not C3aR) reduced Pkd1KO cell proliferation. In conclusion, the loss of Pkd1 promotes unleashed activation of locally produced complement by downregulating DAF expression in renal tubular cells. Increased C5a formation and C5aR1 activation in tubular cells promotes cyst growth, offering a new therapeutic target.
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Affiliation(s)
- Sofia Bin
- Translational Transplant Research Center and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Nephrology, Dialysis and Kidney Transplant Unit, IRCCS Azienda Ospedaliero- University of Bologna, Italy
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum - University of Bologna, Bologna, Italy
| | - Miran Yoo
- Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Paolo Molinari
- Translational Transplant Research Center and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Micaela Gentile
- Translational Transplant Research Center and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Unità Operativa Nefrologia, Azienda-Ospedaliero University of Parma, Department of Medicine and Syrgery, University of Parma, Italy
| | - Kelly Budge
- Translational Transplant Research Center and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Chiara Cantarelli
- Unità Operativa Nefrologia, Azienda-Ospedaliero University of Parma, Department of Medicine and Syrgery, University of Parma, Italy
| | - Yaseen Khan
- Translational Transplant Research Center and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Gaetano La Manna
- Nephrology, Dialysis and Kidney Transplant Unit, IRCCS Azienda Ospedaliero- University of Bologna, Italy
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum - University of Bologna, Bologna, Italy
| | - William M Baldwin
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Nina Dvorina
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Paolo Cravedi
- Translational Transplant Research Center and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - G Luca Gusella
- Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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3
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Joshi N, Garapati K, Ghose V, Kandasamy RK, Pandey A. Recent progress in mass spectrometry-based urinary proteomics. Clin Proteomics 2024; 21:14. [PMID: 38389064 PMCID: PMC10885485 DOI: 10.1186/s12014-024-09462-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/15/2024] [Accepted: 02/12/2024] [Indexed: 02/24/2024] Open
Abstract
Serum or plasma is frequently utilized in biomedical research; however, its application is impeded by the requirement for invasive sample collection. The non-invasive nature of urine collection makes it an attractive alternative for disease characterization and biomarker discovery. Mass spectrometry-based protein profiling of urine has led to the discovery of several disease-associated biomarkers. Proteomic analysis of urine has not only been applied to disorders of the kidney and urinary bladder but also to conditions affecting distant organs because proteins excreted in the urine originate from multiple organs. This review provides a progress update on urinary proteomics carried out over the past decade. Studies summarized in this review have expanded the catalog of proteins detected in the urine in a variety of clinical conditions. The wide range of applications of urine analysis-from characterizing diseases to discovering predictive, diagnostic and prognostic markers-continues to drive investigations of the urinary proteome.
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Affiliation(s)
- Neha Joshi
- Manipal Academy of Higher Education (MAHE), Manipal, 576104, India
- Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India
- Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Kishore Garapati
- Manipal Academy of Higher Education (MAHE), Manipal, 576104, India
- Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India
- Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Vivek Ghose
- Manipal Academy of Higher Education (MAHE), Manipal, 576104, India
- Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India
| | - Richard K Kandasamy
- Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, 55905, USA
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN, 55905, USA
| | - Akhilesh Pandey
- Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India.
- Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, 55905, USA.
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN, 55905, USA.
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4
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Boo YC. Therapeutic Potential and Mechanisms of Rosmarinic Acid and the Extracts of Lamiaceae Plants for the Treatment of Fibrosis of Various Organs. Antioxidants (Basel) 2024; 13:146. [PMID: 38397744 PMCID: PMC10886237 DOI: 10.3390/antiox13020146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/11/2023] [Revised: 01/22/2024] [Accepted: 01/23/2024] [Indexed: 02/25/2024] Open
Abstract
Fibrosis, which causes structural hardening and functional degeneration in various organs, is characterized by the excessive production and accumulation of connective tissue containing collagen, alpha-smooth muscle actin (α-SMA), etc. In traditional medicine, extracts of medicinal plants or herbal prescriptions have been used to treat various fibrotic diseases. The purpose of this narrative review is to discuss the antifibrotic effects of rosmarinic acid (RA) and plant extracts that contain RA, as observed in various experimental models. RA, as well as the extracts of Glechoma hederacea, Melissa officinalis, Elsholtzia ciliata, Lycopus lucidus, Ocimum basilicum, Prunella vulgaris, Salvia rosmarinus (Rosmarinus officinalis), Salvia miltiorrhiza, and Perilla frutescens, have been shown to attenuate fibrosis of the liver, kidneys, heart, lungs, and abdomen in experimental animal models. Their antifibrotic effects were associated with the attenuation of oxidative stress, inflammation, cell activation, epithelial-mesenchymal transition, and fibrogenic gene expression. RA treatment activated peroxisomal proliferator-activated receptor gamma (PPARγ), 5' AMP-activated protein kinase (AMPK), and nuclear factor erythroid 2-related factor 2 (NRF2) while suppressing the transforming growth factor beta (TGF-β) and Wnt signaling pathways. Interestingly, most plants that are reported to contain RA and exhibit antifibrotic activity belong to the family Lamiaceae. This suggests that RA is an active ingredient for the antifibrotic effect of Lamiaceae plants and that these plants are a useful source of RA. In conclusion, accumulating scientific evidence supports the effectiveness of RA and Lamiaceae plant extracts in alleviating fibrosis and maintaining the structural architecture and normal functions of various organs under pathological conditions.
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Affiliation(s)
- Yong Chool Boo
- Department of Molecular Medicine, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu 41944, Republic of Korea;
- BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, The Graduate School, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu 41944, Republic of Korea
- Cell and Matrix Research Institute, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu 41944, Republic of Korea
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5
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Liu A, Luo P, Huang H. New insight of complement system in the process of vascular calcification. J Cell Mol Med 2023; 27:1168-1178. [PMID: 37002701 PMCID: PMC10148053 DOI: 10.1111/jcmm.17732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/22/2022] [Revised: 03/10/2023] [Accepted: 03/14/2023] [Indexed: 04/03/2023] Open
Abstract
The complement system defences against pathogenic microbes and modulates immune homeostasis by interacting with the innate and adaptive immune systems. Dysregulation, impairment or inadvertent activation of complement system contributes to the pathogenesis of some autoimmune diseases and cardiovascular diseases (CVD). Vascular calcification is the pivotal pathological basis of CVD, and contributes to the high morbidity and mortality of CVD. Increasing evidences indicate that the complement system plays a key role in chronic kidney diseases, atherosclerosis, diabetes mellitus and aging-related diseases, which are closely related with vascular calcification. However, the effect of complement system on vascular calcification is still unclear. In this review, we summarize current evidences about the activation of complement system in vascular calcification. We also describe the complex network of complement system and vascular smooth muscle cells osteogenic transdifferentiation, systemic inflammation, endoplasmic reticulum stress, extracellular matrix remodelling, oxidative stress, apoptosis in vascular calcification. Hence, providing a better understanding of the potential relationship between complement system and vascular calcification, so as to provide a direction for slowing the progression of this burgeoning health concern.
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Affiliation(s)
- Aiting Liu
- Department of Cardiology, The Eighth Affiliated Hospital, Joint Laboratory of Guangdong‐Hong Kong‐Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases Sun Yat‐sen University Shenzhen China
| | - Pei Luo
- State Key Laboratory for Quality Research in Chinese Medicines Macau University of Science and Technology Macau China
| | - Hui Huang
- Department of Cardiology, The Eighth Affiliated Hospital, Joint Laboratory of Guangdong‐Hong Kong‐Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases Sun Yat‐sen University Shenzhen China
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6
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Rroji M, Figurek A, Spasovski G. Proteomic Approaches and Potential Applications in Autosomal Dominant Polycystic Kidney Disease and Fabry Disease. Diagnostics (Basel) 2023; 13:1152. [PMID: 36980460 PMCID: PMC10047122 DOI: 10.3390/diagnostics13061152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/02/2023] [Revised: 03/13/2023] [Accepted: 03/13/2023] [Indexed: 03/30/2023] Open
Abstract
Although rare, hereditary diseases, such as autosomal dominant polycystic kidney disease (ADPKD) and Fabry disease (FD) may significantly progress towards severe nephropathy. It is crucial to characterize it accurately, predict the course of the illness and estimate treatment effectiveness. A huge effort has been undertaken to find reliable biomarkers that might be useful for an early prevention of the disease progression and/or any invasive diagnostic procedures. The study of proteomics, or the small peptide composition of a sample, is a field of study under continuous development. Over the past years, several strategies have been created to study and define the proteome of samples from widely varying origins. However, urinary proteomics has become essential for discovering novel biomarkers in kidney disease. Here, the extracellular vesicles in human urine that contain cell-specific marker proteins from every segment of the nephron, offer a source of potentially valuable urinary biomarkers, and may play an essential role in kidney development and kidney disease. This review summarizes the relevant literature investigating the proteomic approaches and potential applications in the regular studies of ADPKD and FD.
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Affiliation(s)
- Merita Rroji
- Department of Nephrology, Faculty of Medicine, University of Medicine Tirana, 1001 Tirana, Albania
| | - Andreja Figurek
- Institute of Anatomy, University of Zurich, 8057 Zurich, Switzerland
| | - Goce Spasovski
- University Clinic for Nephrology, Medical Faculty, University St. Cyril and Methodius, 1000 Skopje, North Macedonia
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7
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Tepus M, Tonoli E, Verderio EAM. Molecular profiling of urinary extracellular vesicles in chronic kidney disease and renal fibrosis. Front Pharmacol 2023; 13:1041327. [PMID: 36712680 PMCID: PMC9877239 DOI: 10.3389/fphar.2022.1041327] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/10/2022] [Accepted: 12/21/2022] [Indexed: 01/13/2023] Open
Abstract
Chronic kidney disease (CKD) is a long-term kidney damage caused by gradual loss of essential kidney functions. A global health issue, CKD affects up to 16% of the population worldwide. Symptoms are often not apparent in the early stages, and if left untreated, CKD can progress to end-stage kidney disease (ESKD), also known as kidney failure, when the only possible treatments are dialysis and kidney transplantation. The end point of nearly all forms of CKD is kidney fibrosis, a process of unsuccessful wound-healing of kidney tissue. Detection of kidney fibrosis, therefore, often means detection of CKD. Renal biopsy remains the best test for renal scarring, despite being intrinsically limited by its invasiveness and sampling bias. Urine is a desirable source of fibrosis biomarkers as it can be easily obtained in a non-invasive way and in large volumes. Besides, urine contains biomolecules filtered through the glomeruli, mirroring the pathological state. There is, however, a problem of highly abundant urinary proteins that can mask rare disease biomarkers. Urinary extracellular vesicles (uEVs), which originate from renal cells and carry proteins, nucleic acids, and lipids, are an attractive source of potential rare CKD biomarkers. Their cargo consists of low-abundant proteins but highly concentrated in a nanosize-volume, as well as molecules too large to be filtered from plasma. Combining molecular profiling data (protein and miRNAs) of uEVs, isolated from patients affected by various forms of CKD, this review considers the possible diagnostic and prognostic value of uEVs biomarkers and their potential application in the translation of new experimental antifibrotic therapeutics.
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Affiliation(s)
- Melanie Tepus
- Centre for Health, Ageing and the Understanding of Disease (CHAUD), School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom
| | - Elisa Tonoli
- Centre for Health, Ageing and the Understanding of Disease (CHAUD), School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom
| | - Elisabetta A. M. Verderio
- Centre for Health, Ageing and the Understanding of Disease (CHAUD), School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom
- Department of Biological, Geological, and Environmental Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy
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8
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Thurman JM, Harrison RA. The susceptibility of the kidney to alternative pathway activation-A hypothesis. Immunol Rev 2023; 313:327-338. [PMID: 36369971 DOI: 10.1111/imr.13168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/15/2022]
Abstract
The glomerulus is often the prime target of dysregulated alternative pathway (AP) activation. In particular, AP activation is the key driver of two severe kidney diseases: atypical hemolytic uremic syndrome and C3 glomerulopathy. Both conditions are associated with a variety of predisposing molecular defects in AP regulation, such as genetic variants in complement regulators, autoantibodies targeting AP proteins, or autoantibodies that stabilize the AP convertases (C3- and C5-activating enzymes). It is noteworthy that these are systemic AP defects, yet in both diseases pathologic complement activation primarily affects the kidneys. In particular, AP activation is often limited to the glomerular capillaries. This tropism of AP-mediated inflammation for the glomerulus points to a unique interaction between AP proteins in plasma and this particular anatomic structure. In this review, we discuss the pre-clinical and clinical data linking the molecular causes of aberrant control of the AP with activation in the glomerulus, and the possible causes of this tropism. Based on these data, we propose a model for why the kidney is so uniquely and frequently targeted in patients with AP defects. Finally, we discuss possible strategies for preventing pathologic AP activation in the kidney.
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Affiliation(s)
- Joshua M Thurman
- Department of Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado, USA
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9
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Song CJ, Li Z, Ahmed UKB, Bland SJ, Yashchenko A, Liu S, Aloria EJ, Lever JM, Gonzalez NM, Bickel MA, Giles CB, Georgescu C, Wren JD, Lang ML, Benveniste EN, Harrington LE, Tsiokas L, George JF, Jones KL, Crossman DK, Agarwal A, Mrug M, Yoder BK, Hopp K, Zimmerman KA. A Comprehensive Immune Cell Atlas of Cystic Kidney Disease Reveals the Involvement of Adaptive Immune Cells in Injury-Mediated Cyst Progression in Mice. J Am Soc Nephrol 2022; 33:747-768. [PMID: 35110364 PMCID: PMC8970461 DOI: 10.1681/asn.2021030278] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/02/2021] [Accepted: 01/16/2022] [Indexed: 11/03/2022] Open
Abstract
BACKGROUND Inducible disruption of cilia-related genes in adult mice results in slowly progressive cystic disease, which can be greatly accelerated by renal injury. METHODS To identify in an unbiased manner modifier cells that may be influencing the differential rate of cyst growth in injured versus non-injured cilia mutant kidneys at a time of similar cyst severity, we generated a single-cell atlas of cystic kidney disease. We conducted RNA-seq on 79,355 cells from control mice and adult-induced conditional Ift88 mice (hereafter referred to as cilia mutant mice) that were harvested approximately 7 months post-induction or 8 weeks post 30-minute unilateral ischemia reperfusion injury. RESULTS Analyses of single-cell RNA-seq data of CD45+ immune cells revealed that adaptive immune cells differed more in cluster composition, cell proportion, and gene expression than cells of myeloid origin when comparing cystic models with one another and with non-cystic controls. Surprisingly, genetic deletion of adaptive immune cells significantly reduced injury-accelerated cystic disease but had no effect on cyst growth in non-injured cilia mutant mice, independent of the rate of cyst growth or underlying genetic mutation. Using NicheNet, we identified a list of candidate cell types and ligands that were enriched in injured cilia mutant mice compared with aged cilia mutant mice and non-cystic controls that may be responsible for the observed dependence on adaptive immune cells during injury-accelerated cystic disease. CONCLUSIONS Collectively, these data highlight the diversity of immune cell involvement in cystic kidney disease.
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Affiliation(s)
- Cheng J. Song
- Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Zhang Li
- Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Ummey Khalecha Bintha Ahmed
- Division of Nephrology, Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Sarah J. Bland
- Division of Nephrology, Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Alex Yashchenko
- Division of Nephrology, Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Shanrun Liu
- Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama
| | - Ernald J. Aloria
- Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Jeremie M. Lever
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - Nancy M. Gonzalez
- Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Marisa A. Bickel
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Cory B. Giles
- Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma
- Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Constantin Georgescu
- Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma
- Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Jonathan D. Wren
- Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma
- Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Mark L. Lang
- Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Etty N. Benveniste
- Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Laurie E. Harrington
- Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Leo Tsiokas
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - James F. George
- Division of Cardiothoracic Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama
| | - Kenneth L. Jones
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - David K. Crossman
- Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama
| | - Anupam Agarwal
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - Michal Mrug
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
- Department of Veterans Affairs Medical Center, Birmingham, Alabama
| | - Bradley K. Yoder
- Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Katharina Hopp
- Polycystic Kidney Disease Program, Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Kurt A. Zimmerman
- Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama
- Division of Nephrology, Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
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10
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Blijdorp CJ, Severs D, Musterd-Bhaggoe UM, Gansevoort RT, Zietse R, Hoorn EJ. Serum bicarbonate is associated with kidney outcomes in autosomal dominant polycystic kidney disease. Nephrol Dial Transplant 2021; 36:2248-2255. [PMID: 33377160 PMCID: PMC8643593 DOI: 10.1093/ndt/gfaa283] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/08/2020] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Metabolic acidosis accelerates progression of chronic kidney disease, but whether this is also true for autosomal dominant polycystic kidney disease (ADPKD) is unknown. METHODS Patients with ADPKD from the DIPAK (Developing Interventions to halt Progression of ADPKD) trial were included [n = 296, estimated glomerular filtration rate (eGFR) 50 ± 11 mL/min/1.73 m2, 2.5 years follow-up]. Outcomes were worsening kidney function (30% decrease in eGFR or kidney failure), annual eGFR change and height-adjusted total kidney and liver volumes (htTKV and htTLV). Cox and linear regressions were adjusted for prognostic markers for ADPKD [Mayo image class and predicting renal outcomes in ADPKD (PROPKD) scores] and acid-base parameters (urinary ammonium excretion). RESULTS Patients in the lowest tertile of baseline serum bicarbonate (23.1 ± 1.6 mmol/L) had a significantly greater risk of worsening kidney function [hazard ratio = 2.95, 95% confidence interval (CI) 1.21-7.19] compared with patients in the highest tertile (serum bicarbonate 29.0 ± 1.3 mmol/L). Each mmol/L decrease in serum bicarbonate increased the risk of worsening kidney function by 21% in the fully adjusted model (hazard ratio = 1.21, 95% CI 1.06-1.37). Each mmol/L decrease of serum bicarbonate was also associated with further eGFR decline (-0.12 mL/min/1.73 m2/year, 95% CI -0.20 to -0.03). Serum bicarbonate was not associated with changes in htTKV or htTLV growth. CONCLUSIONS In patients with ADPKD, a lower serum bicarbonate within the normal range predicts worse kidney outcomes independent of established prognostic factors for ADPKD and independent of urine ammonium excretion. Serum bicarbonate may add to prognostic models and should be explored as a treatment target in ADPKD.
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Affiliation(s)
- Charles J Blijdorp
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, The Netherlands
| | - David Severs
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Usha M Musterd-Bhaggoe
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Ronald T Gansevoort
- Department of Nephrology, University Medical Center Groningen, Groningen, The Netherlands
| | - Robert Zietse
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Ewout J Hoorn
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, The Netherlands
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11
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Lu Q, Hou Q, Cao K, Sun X, Liang Y, Gu M, Xue X, Zhao AZ, Dai C. Complement factor B in high glucose-induced podocyte injury and diabetic kidney disease. JCI Insight 2021; 6:147716. [PMID: 34622800 PMCID: PMC8525650 DOI: 10.1172/jci.insight.147716] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/13/2021] [Accepted: 08/27/2021] [Indexed: 02/06/2023] Open
Abstract
The role and mechanisms for upregulating complement factor B (CFB) expression in podocyte dysfunction in diabetic kidney disease (DKD) are not fully understood. Here, analyzing Gene Expression Omnibus GSE30528 data, we identified genes enriched in mTORC1 signaling, CFB, and complement alternative pathways in podocytes from patients with DKD. In mouse models, podocyte mTOR complex 1 (mTORC1) signaling activation was induced, while blockade of mTORC1 signaling reduced CFB upregulation, alternative complement pathway activation, and podocyte injury in the glomeruli. Knocking down CFB remarkably alleviated alternative complement pathway activation and DKD in diabetic mice. In cultured podocytes, high glucose treatment activated mTORC1 signaling, stimulated STAT1 phosphorylation, and upregulated CFB expression, while blockade of mTORC1 or STAT1 signaling abolished high glucose–upregulated CFB expression. Additionally, high glucose levels downregulated protein phosphatase 2Acα (PP2Acα) expression, while PP2Acα deficiency enhanced high glucose–induced mTORC1/STAT1 activation, CFB induction, and podocyte injury. Taken together, these findings uncover a mechanism by which CFB mediates podocyte injury in DKD.
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Affiliation(s)
| | | | - Kai Cao
- Center for Kidney Disease and
| | - Xiaoli Sun
- Department of Clinical Genetics, Second Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | | | | | - Xian Xue
- Department of Clinical Genetics, Second Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | - Allan Zijian Zhao
- Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, China
| | - Chunsun Dai
- Center for Kidney Disease and.,Department of Clinical Genetics, Second Affiliated Hospital, Nanjing Medical University, Nanjing, China
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12
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Aleš Rigler A, Večerić-Haler Ž, Arnol M, Perše M, Boštjančič E, Pleško J, Simčič S, Kojc N. Exploring the role of the complement system, endothelial injury, and microRNAs in thrombotic microangiopathy after kidney transplantation. J Int Med Res 2021; 48:300060520980530. [PMID: 33372813 PMCID: PMC7783899 DOI: 10.1177/0300060520980530] [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] [Academic Contribution Register] [Indexed: 11/16/2022] Open
Abstract
Objective We investigated whether the recipient’s complement system function, kidney
graft endothelial ultrastructural injury, and microRNA (miRNA) expression
before transplantation may be associated with the risk of posttransplant
de novo thrombotic microangiopathy (TMA). Methods Complement system function assessment, histological and ultrastructural
examination of preimplantation and kidney graft biopsies, and microRNA
assessment were performed on kidney transplant recipients (KTRs) with
de novo TMA. Results On the basis of the clinical course, histological findings, and miRNA
patterns, the following two de novo TMA phenotypes were
observed: a self-limiting disease that was localized to the kidney graft and
a systemic disease that progressed to graft failure without timely
treatment. Decreased alternative complement pathway activity and
ultrastructural endothelial injury before transplantation were confirmed in
all five KTRs and four of five KTRs, respectively, but they did not
correlate with de novo TMA severity. Conclusions Alternative complement pathway abnormalities in KTRs and endothelial
ultrastructural injury on preimplantation biopsy might be associated with
de novo posttransplant TMA, although they did not
predict posttransplant TMA severity (localized vs.
systemic). The specific miRNA expression patterns in preimplantation kidney
graft biopsies demonstrated a borderline statistically significant
difference and might provide more accurate information on posttransplant TMA
severity.
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Affiliation(s)
| | - Željka Večerić-Haler
- Department of Nephrology, University Medical Centre Ljubljana, Slovenia.,Department of Internal Medicine, Faculty of Medicine, University of Ljubljana, Slovenia
| | - Miha Arnol
- Department of Nephrology, University Medical Centre Ljubljana, Slovenia.,Department of Internal Medicine, Faculty of Medicine, University of Ljubljana, Slovenia
| | - Martina Perše
- Medical Experimental Centre, Faculty of Medicine, University of Ljubljana, Slovenia
| | - Emanuela Boštjančič
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Slovenia
| | - Jerica Pleško
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Slovenia
| | - Saša Simčič
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Slovenia
| | - Nika Kojc
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Slovenia
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13
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Maxwell AJ, Ding J, You Y, Dong Z, Chehade H, Alvero A, Mor Y, Draghici S, Mor G. Identification of key signaling pathways induced by SARS-CoV2 that underlie thrombosis and vascular injury in COVID-19 patients. J Leukoc Biol 2021; 109:35-47. [PMID: 33242368 PMCID: PMC7753679 DOI: 10.1002/jlb.4covr0920-552rr] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/01/2020] [Revised: 11/05/2020] [Accepted: 11/05/2020] [Indexed: 12/19/2022] Open
Abstract
The SARS-CoV-2 pandemic has led to hundreds of thousands of deaths and billions of dollars in economic damage. The immune response elicited from this virus is poorly understood. An alarming number of cases have arisen where COVID-19 patients develop complications on top of the symptoms already associated with SARS, such as thrombosis, injuries of vascular system, kidney, and liver, as well as Kawasaki disease. In this review, a bioinformatics approach was used to elucidate the immune response triggered by SARS-CoV-2 infection in primary human lung epithelial and transformed human lung alveolar. Additionally, examined the potential mechanism behind several complications that have been associated with COVID-19 and determined that a specific cytokine storm is leading to excessive neutrophil recruitment. These neutrophils are directly leading to thrombosis, organ damage, and complement activation via neutrophil extracellular trap release.
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Affiliation(s)
- Anthony J Maxwell
- C.S. Mott Center for Human Growth and Development, Department of Obstetrics, Gynecology, Wayne State University, Detroit, Michigan, USA
| | - Jiahui Ding
- C.S. Mott Center for Human Growth and Development, Department of Obstetrics, Gynecology, Wayne State University, Detroit, Michigan, USA
| | - Yuan You
- C.S. Mott Center for Human Growth and Development, Department of Obstetrics, Gynecology, Wayne State University, Detroit, Michigan, USA
| | - Zhong Dong
- C.S. Mott Center for Human Growth and Development, Department of Obstetrics, Gynecology, Wayne State University, Detroit, Michigan, USA
| | - Hussein Chehade
- C.S. Mott Center for Human Growth and Development, Department of Obstetrics, Gynecology, Wayne State University, Detroit, Michigan, USA
| | - Ayesha Alvero
- C.S. Mott Center for Human Growth and Development, Department of Obstetrics, Gynecology, Wayne State University, Detroit, Michigan, USA
| | - Yechiel Mor
- Department of Internal Medicine Wayne State University, Detroit, Michigan, USA
| | - Sorin Draghici
- Department of Computer Science, Wayne State University, Detroit, Michigan, USA
| | - Gil Mor
- C.S. Mott Center for Human Growth and Development, Department of Obstetrics, Gynecology, Wayne State University, Detroit, Michigan, USA
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14
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Strubl S, Torres JA, Spindt AK, Pellegrini H, Liebau MC, Weimbs T. STAT signaling in polycystic kidney disease. Cell Signal 2020; 72:109639. [PMID: 32325185 PMCID: PMC7269822 DOI: 10.1016/j.cellsig.2020.109639] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/13/2020] [Revised: 04/13/2020] [Accepted: 04/14/2020] [Indexed: 02/06/2023]
Abstract
The most common form of polycystic kidney disease (PKD) in humans is caused by mutations in the PKD1 gene coding for polycystin1 (PC1). Among the many identified or proposed functions of PC1 is its ability to regulate the activity of transcription factors of the STAT family. Most STAT proteins that have been investigated were found to be aberrantly activated in kidneys in PKD, and some have been shown to be drivers of disease progression. In this review, we focus on the role of signal transducer and activator of transcription (STAT) signaling pathways in various renal cell types in healthy kidneys as compared to polycystic kidneys, on the mechanisms of STAT regulation by PC1 and other factors, and on the possibility to target STAT signaling for PKD therapy.
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Affiliation(s)
- Sebastian Strubl
- Department of Molecular, Cellular, and Developmental Biology, Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA 93106-9625, USA; Department II of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Jacob A Torres
- Department of Molecular, Cellular, and Developmental Biology, Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA 93106-9625, USA
| | - Alison K Spindt
- Department of Molecular, Cellular, and Developmental Biology, Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA 93106-9625, USA
| | - Hannah Pellegrini
- Department of Molecular, Cellular, and Developmental Biology, Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA 93106-9625, USA
| | - Max C Liebau
- Department of Pediatrics and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Department II of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Thomas Weimbs
- Department of Molecular, Cellular, and Developmental Biology, Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA 93106-9625, USA.
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15
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Zimmerman KA, Hopp K, Mrug M. Role of chemokines, innate and adaptive immunity. Cell Signal 2020; 73:109647. [PMID: 32325183 DOI: 10.1016/j.cellsig.2020.109647] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/07/2020] [Revised: 04/16/2020] [Accepted: 04/16/2020] [Indexed: 02/06/2023]
Abstract
Polycystic Kidney Disease (PKD) triggers a robust immune system response including changes in both innate and adaptive immunity. These changes involve immune cells (e.g., macrophages and T cells) as well as cytokines and chemokines (e.g., MCP-1) that regulate the production, differentiation, homing, and various functions of these cells. This review is focused on the role of the immune system and its associated factors in the pathogenesis of PKDs as evidenced by data from cell-based systems, animal models, and PKD patients. It also highlights relevant pre-clinical and clinical studies that point to specific immune system components as promising candidates for the development of prognostic biomarkers and therapeutic strategies to improve PKD outcomes.
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Affiliation(s)
- Kurt A Zimmerman
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Division of Nephrology, Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Katharina Hopp
- Department of Medicine, Division of Renal Diseases and Hypertension, Polycystic Kidney Disease Program, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Michal Mrug
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Department of Veterans Affairs Medical Center, Birmingham, AL 35233, USA.
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16
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Proteomic Analysis of Urinary Extracellular Vesicles Reveals a Role for the Complement System in Medullary Sponge Kidney Disease. Int J Mol Sci 2019; 20:ijms20215517. [PMID: 31694344 PMCID: PMC6862015 DOI: 10.3390/ijms20215517] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/12/2019] [Revised: 10/15/2019] [Accepted: 11/04/2019] [Indexed: 12/15/2022] Open
Abstract
Medullary sponge kidney (MSK) disease is a rare and neglected kidney condition often associated with nephrocalcinosis/nephrolithiasis and cystic anomalies in the precalyceal ducts. Little is known about the pathogenesis of this disease, so we addressed the knowledge gap using a proteomics approach. The protein content of microvesicles/exosomes isolated from urine of 15 MSK and 15 idiopathic calcium nephrolithiasis (ICN) patients was investigated by mass spectrometry, followed by weighted gene co-expression network analysis, support vector machine (SVM) learning, and partial least squares discriminant analysis (PLS-DA) to select the most discriminative proteins. Proteomic data were verified by ELISA. We identified 2998 proteins in total, 1764 (58.9%) of which were present in both vesicle types in both diseases. Among the MSK samples, only 65 (2.2%) and 137 (4.6%) proteins were exclusively found in the microvesicles and exosomes, respectively. Similarly, among the ICN samples, only 75 (2.5%) and 94 (3.1%) proteins were exclusively found in the microvesicles and exosomes, respectively. SVM learning and PLS-DA revealed a core panel of 20 proteins that distinguished extracellular vesicles representing each clinical condition with an accuracy of 100%. Among them, three exosome proteins involved in the lectin complement pathway maximized the discrimination between MSK and ICN: Ficolin 1, Mannan-binding lectin serine protease 2, and Complement component 4-binding protein β. ELISA confirmed the proteomic results. Our data show that the complement pathway is involved in the MSK, revealing a new range of potential therapeutic targets and early diagnostic biomarkers.
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17
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Xue C, Mei CL. Polycystic Kidney Disease and Renal Fibrosis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1165:81-100. [PMID: 31399962 DOI: 10.1007/978-981-13-8871-2_5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 12/13/2022]
Abstract
Polycystic kidney disease (PKD) is a common genetic disorder characterized by formations of numerous cysts in kidneys and most caused by PKD1 or PKD2 mutations in autosomal dominant polycystic kidney disease (ADPKD). The interstitial inflammation and fibrosis is one of the major pathological changes in polycystic kidney tissues with an accumulation of inflammatory cells, chemokines, and cytokines. The immune response is observed across different stages and occurs prior to or coincident with cyst formation in ADPKD. Evidence for inflammation as an important contributor to cyst growth and fibrosis includes increased interstitial macrophages, upregulated expressions of pro-inflammatory cytokines, activated complement system, and activated pathways including NF-κB and JAK-STAT signaling in polycystic kidney tissues. Inflammatory cells are responsible for overproduction of several pro-fibrotic growth factors which promote renal fibrosis in ADPKD. These growth factors trigger epithelial mesenchymal transition and myofibroblast/fibrocyte activation, which stimulate the expansion of extracellular matrix (ECM) including collagen I, III, IV, V, and fibronectin, leading to renal fibrosis and reduced renal function. Besides, there are imbalanced ECM turnover regulators which lead to the increased ECM production and inadequate degradation in polycystic kidney tissues. Several fibrosis associated signaling pathways, such as TGFβ-SMAD, Wnt, and periostin-integrin-linked kinase are also activated in polycystic kidney tissues. Although the effective anti-fibrotic treatments are limited at the present time, slowing the cyst expansion and fibrosis development is very important for prolonging life span and improving the palliative care of ADPKD patients. The inhibition of pro-fibrotic cytokines involved in fibrosis might be a new therapeutic strategy for ADPKD in the future.
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Affiliation(s)
- Cheng Xue
- Division of Nephrology, Kidney Institute of PLA, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Chang-Lin Mei
- Division of Nephrology, Kidney Institute of PLA, Changzheng Hospital, Second Military Medical University, Shanghai, China.
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18
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Li Q, Li H, Shi J, He B, Yu F. Complement alternative pathway activation associated with pulmonary hypertension in lupus nephritis patients. Lupus 2019; 28:1051-1061. [PMID: 31296141 DOI: 10.1177/0961203319860192] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/16/2022]
Abstract
Pulmonary hypertension occurs in systemic lupus erythematosus (SLE) for several reasons, such as vasculopathy. Previous studies have indicated that the excessive activation of the complement alternative pathway might be involved in the pathogenesis of lupus nephritis, especially in the absence of factor H or its functional impairment. However, the clinical and pathological significance of the alternative complement activation in lupus nephritis patients with pulmonary hypertension remains elusive. The data on patients with pulmonary hypertension and non-pulmonary hypertension lupus nephritis were retrospectively analyzed in our centre. Major plasma levels of complement components were evaluated. The depositions of Bb, C3d and C5b-9 in the lung specimens of pulmonary hypertension combined with SLE patients were detected by immunofluorescence staining. Among 352 lupus nephritis cases, 24 were diagnosed with pulmonary hypertension and 328 with non-pulmonary hypertension. Higher levels of Bb and lower levels of factor H were detected in the pulmonary hypertension group in comparison with the negative group (P = 0.049, P = 0.024, respectively). Pulmonary hypertension was a risk factor for renal outcome as deduced by the log-rank and Cox test for survival analysis. C3d, C5b-9 and Bb were found to be positive in lung specimens of lupus nephritis patients with pulmonary hypertension. We concluded that activation of the complement alternative pathway may be involved in the pathogenesis of pulmonary hypertension in lupus nephritis.
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Affiliation(s)
- Q Li
- 1 Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing, China
| | - H Li
- 2 MOE Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Xi'an, China
| | - J Shi
- 2 MOE Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Xi'an, China
| | - B He
- 1 Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing, China
| | - F Yu
- 3 Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,4 Department of Nephrology, Peking University International Hospital, Beijing, China
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19
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Tubular cell and keratinocyte single-cell transcriptomics applied to lupus nephritis reveal type I IFN and fibrosis relevant pathways. Nat Immunol 2019; 20:915-927. [PMID: 31110316 PMCID: PMC6584054 DOI: 10.1038/s41590-019-0386-1] [Citation(s) in RCA: 278] [Impact Index Per Article: 46.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/18/2018] [Accepted: 03/26/2019] [Indexed: 12/22/2022]
Abstract
The molecular and cellular processes that lead to renal damage and to the heterogeneity of lupus nephritis (LN) are not well understood. We applied single-cell RNA sequencing (scRNA-seq) to renal biopsies from patients with LN and evaluated skin biopsies as a potential source of diagnostic and prognostic markers of renal disease. Type I interferon (IFN) response signatures in tubular cells and in keratinocytes distinguished patients with LN from healthy control subjects. Moreover, a high IFN response signature and fibrotic signature in tubular cells were each associated with failure to respond to treatment. Analysis of tubular cells from patients with proliferative, membranous, and mixed LN indicated pathways relevant to inflammation and fibrosis, which offer insight into their histological differences. In summary, we applied scRNA-seq to LN to deconstruct its heterogeneity and identify novel targets for personalized approaches to therapy.
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20
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Li H, Zhang Y, Dan J, Zhou R, Li C, Li R, Wu X, Kumar Singh S, T Chang J, Yang J, Luo Y. p53 mutation regulates PKD genes and results in co-occurrence of PKD and tumorigenesis. Cancer Biol Med 2019; 16:79-102. [PMID: 31119048 PMCID: PMC6528458 DOI: 10.20892/j.issn.2095-3941.2018.0170] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 02/04/2023] Open
Abstract
Objective Polycystic kidney disease (PKD) is the major cause of kidney failure and mortality in humans. It has always been suspected that the development of cystic kidney disease shares features with tumorigenesis, although the evidence is unclear. Methods We crossed p53 mutant mice (p53N236S, p53S) with Werner syndrome mice and analyzed the pathological phenotypes. The RNA-seq, ssGSEA analysis, and real-time PCR were performed to dissect the gene signatures involved in the development of disease phenotypes. Results We found enlarged kidneys with fluid-filled cysts in offspring mice with a genotype of G3mTerc-/-WRN-/-p53S/S (G3TM). Pathology analysis confirmed the occurrence of PKD, and it was highly correlated with the incidence of tumorigenesis. RNA-seq data revealed the gene signatures involved in PKD development, and demonstrated that PKD and tumorigenesis shared common pathways, including complement pathways, lipid metabolism, mitochondria energy homeostasis and others. Interestingly, this G3TM PKD and the classical PKD1/2 deficient PKD shared common pathways, possibly because the mutant p53S could regulate the expression levels of PKD1/2, Pkhd1, and Hnf1b.
Conclusions We established a dual mouse model for PKD and tumorigenesis derived from abnormal cellular proliferation and telomere dysfunction. The innovative point of our study is to report PKD occurring in conjunction with tumorigenesis. The gene signatures revealed might shed new light on the pathogenesis of PKD, and provide new molecular biomarkers for clinical diagnosis and prognosis.
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Affiliation(s)
- Haili Li
- Faculty of Environmental Science and Engineering, Kunming University of Science and Technology, Kunming 650500, China.,Laboratory of Molecular Genetics of Aging & Tumor, Kunming University of Science and Technology, Kunming 650500, China
| | - Yongjin Zhang
- Laboratory of Molecular Genetics of Aging & Tumor, Kunming University of Science and Technology, Kunming 650500, China
| | - Juhua Dan
- Laboratory of Molecular Genetics of Aging & Tumor, Kunming University of Science and Technology, Kunming 650500, China
| | - Ruoyu Zhou
- Laboratory of Molecular Genetics of Aging & Tumor, Kunming University of Science and Technology, Kunming 650500, China
| | - Cui Li
- Laboratory of Molecular Genetics of Aging & Tumor, Kunming University of Science and Technology, Kunming 650500, China
| | - Rong Li
- Division of Nephrology, The First People's Hospital of Yunnan Province, Kunming 650032, China
| | - Xiaoming Wu
- Laboratory of Molecular Genetics of Aging & Tumor, Kunming University of Science and Technology, Kunming 650500, China
| | - Sanjay Kumar Singh
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston 77030, TX, USA
| | - Jeffrey T Chang
- Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston 77030, TX, USA
| | - Julun Yang
- Department of Pathology, Kunming General Hospital, Kunming 650032, China
| | - Ying Luo
- Faculty of Environmental Science and Engineering, Kunming University of Science and Technology, Kunming 650500, China.,Laboratory of Molecular Genetics of Aging & Tumor, Kunming University of Science and Technology, Kunming 650500, China
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21
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Yang Y, Chen M, Zhou J, Lv J, Song S, Fu L, Chen J, Yang M, Mei C. Interactions between Macrophages and Cyst-Lining Epithelial Cells Promote Kidney Cyst Growth in Pkd1-Deficient Mice. J Am Soc Nephrol 2018; 29:2310-2325. [PMID: 30042193 DOI: 10.1681/asn.2018010074] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/20/2018] [Accepted: 06/21/2018] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Autosomal-dominant polycystic kidney disease (ADPKD) is the leading inherited renal disease worldwide. The proproliferative function of macrophages is associated with late-stage cyst enlargement in mice with PKD; however, the way in which macrophages act on cyst-lining epithelial cells (CLECs) has not been well elucidated. METHODS We generated a rapid-onset PKD mouse model by inactivating Pkd1 on postnatal day 10 (P10) and compared cell proliferation and differential gene expression in kidney tissues of the PKD mice and wild-type (WT) littermates. RESULTS The cystic phenotype was dominant from P18. A distinct peak in cell proliferation in polycystic kidneys during P22-P30 was closely related to late-stage cyst growth. Comparisons of gene expression profiles in kidney tissues at P22 and P30 in PKD and WT mice revealed that arginine metabolism was significantly activated; 204 differentially expressed genes (DEGs), including Arg1, an arginine metabolism-associated gene, were identified in late-stage polycystic kidneys. The Arg1-encoded protein, arginase-1 (ARG1), was predominantly expressed in macrophages in a time-dependent manner. Multiple-stage macrophage depletion verified that macrophages expressing high ARG1 levels accounted for late-stage cyst enlargement, and inhibiting ARG1 activity significantly retarded cyst growth and effectively lowered the proliferative indices in polycystic kidneys. In vitro experiments revealed that macrophages stimulated CLEC proliferation, and that L-lactic acid, primarily generated by CLECs, significantly upregulated ARG1 expression and increased polyamine synthesis in macrophages. CONCLUSIONS Interactions between macrophages and CLECs promote cyst growth. ARG1 is a key molecule involved in this process and is a potential therapeutic target to help delay ADPKD progression.
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Affiliation(s)
- Yang Yang
- Division of Nephrology, Kidney Institution of Chinese People's Liberation Army (PLA), Chang Zheng Hospital, The Second Military Medical University, Shanghai, China.,Division of Nephrology, Kidney Diagnostic and Therapeutic Center of PLA, Beidaihe Sanatorium of PLA, Qinhuangdao, China; and
| | - Meihan Chen
- Division of Nephrology, Kidney Institution of Chinese People's Liberation Army (PLA), Chang Zheng Hospital, The Second Military Medical University, Shanghai, China
| | - Jie Zhou
- Division of Nephrology, Kidney Institution of Chinese People's Liberation Army (PLA), Chang Zheng Hospital, The Second Military Medical University, Shanghai, China
| | - Jiayi Lv
- Division of Nephrology, Kidney Institution of Chinese People's Liberation Army (PLA), Chang Zheng Hospital, The Second Military Medical University, Shanghai, China
| | - Shuwei Song
- Division of Nephrology, Kidney Institution of Chinese People's Liberation Army (PLA), Chang Zheng Hospital, The Second Military Medical University, Shanghai, China
| | - LiLi Fu
- Division of Nephrology, Kidney Institution of Chinese People's Liberation Army (PLA), Chang Zheng Hospital, The Second Military Medical University, Shanghai, China
| | - Jiejian Chen
- Division of Nephrology, Kidney Institution of Chinese People's Liberation Army (PLA), Chang Zheng Hospital, The Second Military Medical University, Shanghai, China.,Department of Nephrology, The 175th Hospital of PLA, Zhangzhou, China
| | - Ming Yang
- Division of Nephrology, Kidney Institution of Chinese People's Liberation Army (PLA), Chang Zheng Hospital, The Second Military Medical University, Shanghai, China
| | - Changlin Mei
- Division of Nephrology, Kidney Institution of Chinese People's Liberation Army (PLA), Chang Zheng Hospital, The Second Military Medical University, Shanghai, China;
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Orton DJ, Doucette AA, Huang WY, MacLellan DL. Exosomal proteomic analysis reveals changes in the urinary proteome of rats with unilateral ureteral obstruction. CAN J CHEM 2018. [DOI: 10.1139/cjc-2017-0681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/22/2022]
Abstract
Congenital urinary tract obstruction (UTO) is a commonly noted disorder with the potential to cause permanent loss of renal function. Due to the possibility of spontaneous resolution, postnatal management strategies require lengthy and invasive surveillance methods to monitor the status of renal function and severity of obstruction. Here, a quantitative proteome analysis of urinary exosomes from weanling rats with surgically introduced UTO identifies a number of candidate biomarkers with the potential to improve diagnostic and prognostic methods for this disease. Using gel-assisted digestion coupled to liquid chromatography/tandem mass spectrometry (LC–MS/MS), 318 proteins were identified. Relative protein quantitation by spectral counting showed 190 proteins with significant changes in abundance due to either partial or complete obstruction. Numerous proteins identified here have been shown to be similarly altered in abundance in other renal diseases that cause tubule apoptosis and interstitial fibrosis. Extrapolating the role of the proteins showing quantifiable changes in abundance here from other forms of renal disease suggests they have potential for clinical applicability as biomarkers of congenital UTO. Included in the list of identified proteins are markers of apoptosis, oxidative stress, fibrosis, inflammation, and tubular cell damage, which are commonly associated with UTO. This study therefore provides a number of candidate biomarkers that, following validation in children experiencing UTO, have the potential to improve postnatal management of this disease.
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Affiliation(s)
- Dennis J. Orton
- Department of Pathology, Dalhousie University, 11th Floor Tupper Medical Building, Room 11B, Halifax, NS B3H 4R2, Canada
| | - Alan A. Doucette
- Department of Chemistry, Dalhousie University, Room 212, Chemistry Building, Halifax, NS B3H 4R2, Canada
| | - Weei-Yuarn Huang
- Department of Pathology, 5788 University Avenue, MacKenzie Building Room 717, Halifax, NS B3H 1V8, Canada
| | - Dawn L. MacLellan
- Department of Urology, 1st Floor IWK Health Centre, 5850 University Avenue, Halifax, NS B3J 3G9, Canada
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Chan EYH, Warady BA. Acquired cystic kidney disease: an under-recognized condition in children with end-stage renal disease. Pediatr Nephrol 2018; 33:41-51. [PMID: 28444445 DOI: 10.1007/s00467-017-3649-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 11/30/2016] [Revised: 03/04/2017] [Accepted: 03/07/2017] [Indexed: 12/27/2022]
Abstract
Acquired cystic kidney disease (ACKD) is a condition that occurs predominantly in patients with end-stage renal disease (ESRD). In contrast to hereditary cystic kidney disease, ACKD is characterized by the presence of multiple small cysts in bilaterally small kidneys. Limited pediatric data suggest a high incidence (21.6-45.8%) of ACKD in children on dialysis, comparable to that in adults, with an increased frequency associated with a longer duration of dialysis. Recent research has shed light on the pathogenesis of ACKD, such as activation of proto-oncogenes. Although most patients with ACKD are asymptomatic, the condition can be complicated by renal cell carcinoma. Routine surveillance should therefore be considered in at-risk populations.
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Affiliation(s)
- Eugene Y H Chan
- Children's Mercy Hospital, 2401 Gillham Road, Kansas City, MO, 64108, USA
| | - Bradley A Warady
- Children's Mercy Hospital, 2401 Gillham Road, Kansas City, MO, 64108, USA.
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24
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Chatterjee S, Verma SP, Pandey P. Profiling conserved biological pathways in Autosomal Dominant Polycystic Kidney Disorder (ADPKD) to elucidate key transcriptomic alterations regulating cystogenesis: A cross-species meta-analysis approach. Gene 2017; 627:434-450. [DOI: 10.1016/j.gene.2017.06.059] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/13/2017] [Revised: 06/28/2017] [Accepted: 06/30/2017] [Indexed: 12/16/2022]
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25
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Choi YW, Kim YG, Song MY, Moon JY, Jeong KH, Lee TW, Ihm CG, Park KS, Lee SH. Potential urine proteomics biomarkers for primary nephrotic syndrome. Clin Proteomics 2017; 14:18. [PMID: 28522940 PMCID: PMC5434615 DOI: 10.1186/s12014-017-9153-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/02/2016] [Accepted: 05/06/2017] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Nephrotic syndrome (NS) is a nonspecific kidney disorder, commonly caused by minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), and membranous nephropathy (MN). Here we analyzed urinary protein profiles, aiming to discover disease-specific biomarkers of these three common diseases in NS. METHODS Sixteen urine samples were collected from patients with biopsy-proven NS and healthy controls. After removal of high-abundance proteins, the urinary protein profile was analyzed by LC-MS/MS to generate a discovery set. For validation, ELISA was used to analyze the selected proteins in 61 urine samples. RESULTS The discovery set included 228 urine proteins, of which 22 proteins were differently expressed in MCD, MN, and FSGS. Among these, C9, CD14, and SERPINA1 were validated by ELISA. All three proteins were elevated in MCD, MN, and FSGS groups compared with in IgA nephropathy and healthy controls. When a regression model was applied, receiver operating characteristic analysis clearly discriminated MCD from the other causative diseases in NS. CONCLUSIONS We developed a disease-specific protein panel that discriminated between three main causes of NS. Through this pilot study, we suggest that urine proteomics could be a non-invasive and clinically available tool to discriminate MCD from MN and FSGS.
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Affiliation(s)
- Young Wook Choi
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, 892 Dongnam-ro, Gangdong-gu, Seoul, Korea
| | - Yang Gyun Kim
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, 892 Dongnam-ro, Gangdong-gu, Seoul, Korea
| | - Min-Young Song
- Department of Physiology, Kyung Hee University School of Medicine, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, Korea
| | - Ju-Young Moon
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, 892 Dongnam-ro, Gangdong-gu, Seoul, Korea
| | - Kyung-Hwan Jeong
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, 892 Dongnam-ro, Gangdong-gu, Seoul, Korea
| | - Tae-Won Lee
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, 892 Dongnam-ro, Gangdong-gu, Seoul, Korea
| | - Chun-Gyoo Ihm
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, 892 Dongnam-ro, Gangdong-gu, Seoul, Korea
| | - Kang-Sik Park
- Department of Physiology, Kyung Hee University School of Medicine, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, Korea
| | - Sang-Ho Lee
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, 892 Dongnam-ro, Gangdong-gu, Seoul, Korea
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26
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Li Y, Tian X, Ma M, Jerman S, Kong S, Somlo S, Sun Z. Deletion of ADP Ribosylation Factor-Like GTPase 13B Leads to Kidney Cysts. J Am Soc Nephrol 2016; 27:3628-3638. [PMID: 27153923 PMCID: PMC5118478 DOI: 10.1681/asn.2015091004] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/10/2015] [Accepted: 03/08/2016] [Indexed: 12/14/2022] Open
Abstract
The gene for ADP ribosylation factor-like GTPase 13B (Arl13b) encodes a small GTPase essential for cilia biogenesis in multiple model organisms. Inactivation of arl13b in zebrafish leads to a number of phenotypes indicative of defective cilia, including cystic kidneys. In mouse, null mutation in Arl13b results in severe patterning defects in the neural tube and defective Hedgehog signaling. Human mutations of ARL13B lead to Joubert syndrome, a ciliopathy. However, patients with mutated ARL13B do not develop kidney cysts. To investigate whether Arl13b has a role in ciliogenesis in mammalian kidney and whether loss of function of Arl13b leads to cystic kidneys in mammals, we generated a mouse model with kidney-specific conditional knockout of Arl13b Deletion of Arl13b in the distal nephron at the perinatal stage led to a cilia biogenesis defect and rapid kidney cyst formation. Additionally, we detected misregulation of multiple pathways in the cystic kidneys of this model. Moreover, valproic acid, a histone deacetylase inhibitor that we previously showed slows cyst progression in a mouse cystic kidney model with neonatal inactivation of Pkd1, inhibited the early rise of Wnt7a expression, ameliorated fibrosis, slowed cyst progression, and improved kidney function in the Arl13b mutant mouse. Finally, in rescue experiments in zebrafish, all ARL13B allele combinations identified in patients with Joubert syndrome provided residual Arl13b function, supporting the idea that the lack of cystic kidney phenotype in human patients with ARL13B mutations is explained by the hypomorphic nature of the mutations.
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Affiliation(s)
| | - Xin Tian
- Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Ming Ma
- Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | | | | | - Stefan Somlo
- Departments of *Genetics and
- Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
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27
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Caplan MJ. The tail of polycystin-1 pays the kidney a complement. Am J Physiol Renal Physiol 2016; 310:F1180-1. [DOI: 10.1152/ajprenal.00141.2016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/22/2022] Open
Affiliation(s)
- Michael J. Caplan
- Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut
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28
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Wu M, Gu J, Mei S, Xu D, Jing Y, Yao Q, Chen M, Yang M, Chen S, Yang B, Qi N, Hu H, Wüthrich RP, Mei C. Resveratrol delays polycystic kidney disease progression through attenuation of nuclear factor κB-induced inflammation. Nephrol Dial Transplant 2016; 31:1826-1834. [PMID: 27190325 DOI: 10.1093/ndt/gfw058] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/29/2015] [Accepted: 02/24/2016] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Inflammation plays an important role in polycystic kidney disease (PKD). The current study aimed to examine the efficacy of the anti-inflammatory compound resveratrol in PKD and to investigate its underlying mechanism of action. METHODS Male Han:SPRD (Cy/+) rats with PKD were treated with 200 mg/kg/day resveratrol or vehicle by gavage for 5 weeks. Human autosomal dominant (AD) PKD cells, three-dimensional (3D) Madin-Darby canine kidney cells and zebrafish were treated with various concentrations of resveratrol or the nuclear factor κB (NF-κB) inhibitor QNZ. RESULTS Resveratrol treatment reduced blood urea nitrogen levels and creatinine levels by 20 and 24%, respectively, and decreased two-kidney/total body weight ratio by 15% and cyst volume density by 24% in Cy/+ rats. The proliferation index and the macrophage infiltration index were reduced by 40 and 43%, respectively, in resveratrol-treated cystic kidneys. Resveratrol reduced the levels of the pro-inflammatory factors monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α) and complement factor B (CFB) in Cy/+ rat kidneys in parallel with the decreased activity of NF-κB (p50/p65). The activation of NF-κB and its correlation with pro-inflammatory factor expression were confirmed in human ADPKD cells and kidney tissues. Resveratrol and QNZ inhibited the expression of MCP-1, TNF-α and CFB and reduced NF-κB activity in ADPKD cells. Moreover, NF-κB blockage minimized the inhibition of inflammatory factor production by resveratrol treatment. Furthermore, resveratrol or QNZ inhibited cyst formation in the 3D cyst and zebrafish models. CONCLUSIONS The NF-κB signaling pathway is activated and partly responsible for inflammation in polycystic kidney tissues. Targeting inflammation through resveratrol could be a new strategy for PKD treatment in the future.
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Affiliation(s)
- Ming Wu
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Junhui Gu
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Shuqin Mei
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Dechao Xu
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Ying Jing
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Qing Yao
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Meihan Chen
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Ming Yang
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Sixiu Chen
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Bo Yang
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Na Qi
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Huimin Hu
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | | | - Changlin Mei
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
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29
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Wu M, Chen M, Jing Y, Gu J, Mei S, Yao Q, Zhou J, Yang M, Sun L, Wang W, Hu H, Wüthrich RP, Mei C. The C-terminal tail of polycystin-1 regulates complement factor B expression by signal transducer and activator of transcription 1. Am J Physiol Renal Physiol 2016; 310:F1284-94. [PMID: 26984954 DOI: 10.1152/ajprenal.00428.2015] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/21/2015] [Accepted: 03/07/2016] [Indexed: 01/12/2023] Open
Abstract
Inhibition of the overactivated alternative complement pathway in autosomal dominant polycystic kidney disease (ADPKD) retards disease progression in animal models; however, it remains unknown how complement factor B (CFB) is upregulated in ADPKD. Here, we showed that the overexpression of CFB in cystic kidneys is associated with increased JAK2/STAT1 activity and enhanced expression of the polycystin-1 C-terminal tail (PC1-CTT). Overexpression or blockage of STAT1 increased or decreased CFB expression and CFB promoter activity. Moreover, overexpression of PC1-CTT induced JAK2/STAT1 activation and CFB upregulation in renal tubular epithelial cells. Furthermore, PC1-CTT overexpression increased human CFB promoter activity, whereas dominant negative STAT1 plasmids or mutation of putative STAT1 responsive elements decreased PC1-CTT-induced CFB promoter activity. The effect of CFB on macrophage differentiation was tested on a mouse macrophage cell line. Bioactive CFB dose dependently promoted macrophage M2 phenotype conversion. In addition, conditioned media from renal epithelial cells promoted macrophage M2 phenotype conversion which was blocked by STAT1 inhibition in a dose-dependent manner. Conditioned media from PC1-CTT-transfected renal epithelial cells further promoted macrophage M2 phenotype conversion, which was suppressed by fludarabine or a CFB antibody. In addition, we show that NF-κB acts downstream of PC1-CTT and may partly mediate PC1-CTT-induced CFB expression. In conclusion, our study reveals possible mechanisms of CFB upregulation in ADPKD and a novel role of PC1-CTT in ADPKD-associated inflammation. Furthermore, our study suggests that targeting STAT1 may be a new strategy to prevent inflammation in the kidney of patients with ADPKD.
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Affiliation(s)
- Ming Wu
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Meihan Chen
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China;
| | - Ying Jing
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China; Department of Blood Purification, General Hospital of Jinan Military Command of PLA, Shandong, China; and
| | - Junhui Gu
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Shuqin Mei
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Qing Yao
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Jie Zhou
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Ming Yang
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Lijun Sun
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Wutao Wang
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Huimin Hu
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | | | - Changlin Mei
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
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Salih M, Demmers JA, Bezstarosti K, Leonhard WN, Losekoot M, van Kooten C, Gansevoort RT, Peters DJM, Zietse R, Hoorn EJ. Proteomics of Urinary Vesicles Links Plakins and Complement to Polycystic Kidney Disease. J Am Soc Nephrol 2016; 27:3079-3092. [PMID: 26940098 DOI: 10.1681/asn.2015090994] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/08/2015] [Accepted: 01/19/2015] [Indexed: 12/21/2022] Open
Abstract
Novel therapies in autosomal dominant polycystic kidney disease (ADPKD) signal the need for markers of disease progression or response to therapy. This study aimed to identify disease-associated proteins in urinary extracellular vesicles (uEVs), which include exosomes, in patients with ADPKD. We performed quantitative proteomics on uEVs from healthy controls and patients with ADPKD using a labeled approach and then used a label-free approach with uEVs of different subjects (healthy controls versus patients with ADPKD versus patients with non-ADPKD CKD). In both experiments, 30 proteins were consistently more abundant (by two-fold or greater) in ADPKD-uEVs than in healthy- and CKD-uEVs. Of these proteins, we selected periplakin, envoplakin, villin-1, and complement C3 and C9 for confirmation because they were also significantly overrepresented in pathway analysis and were previously implicated in ADPKD pathogenesis. Immunoblotting confirmed higher abundances of the selected proteins in uEVs from three independent groups of patients with ADPKD. Whereas uEVs of young patients with ADPKD and preserved kidney function already had higher levels of complement, only uEVs of patients with advanced stages of ADPKD had increased levels of villin-1, periplakin, and envoplakin. Furthermore, all five proteins correlated positively with total kidney volume. Analysis in kidney tissue from mice with kidney-specific, tamoxifen-inducible Pkd1 deletion demonstrated higher expression in more severe stages of the disease and correlation with kidney weight for each protein of interest. In summary, proteomic analysis of uEVs identified plakins and complement as disease-associated proteins in ADPKD. These proteins are new candidates for evaluation as biomarkers or targets for therapy in ADPKD.
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Affiliation(s)
- Mahdi Salih
- Department of Internal Medicine, Division of Nephrology & Transplantation, and
| | - Jeroen A Demmers
- Proteomics Center, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Karel Bezstarosti
- Proteomics Center, Erasmus Medical Center, Rotterdam, The Netherlands
| | | | | | - Cees van Kooten
- Nephrology, Leiden University Medical Center, Leiden, The Netherlands; and
| | - Ron T Gansevoort
- Department of Nephrology, University Medical Center Groningen, Groningen, The Netherlands
| | | | - Robert Zietse
- Department of Internal Medicine, Division of Nephrology & Transplantation, and
| | - Ewout J Hoorn
- Department of Internal Medicine, Division of Nephrology & Transplantation, and
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31
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Akoh JA. Current management of autosomal dominant polycystic kidney disease. World J Nephrol 2015; 4:468-479. [PMID: 26380198 PMCID: PMC4561844 DOI: 10.5527/wjn.v4.i4.468] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 06/01/2015] [Revised: 06/23/2015] [Accepted: 08/31/2015] [Indexed: 02/06/2023] Open
Abstract
Autosomal dominant polycystic kidney disease (ADPKD), the most frequent cause of genetic renal disease affecting approximately 4 to 7 million individuals worldwide and accounting for 7%-15% of patients on renal replacement therapy, is a systemic disorder mainly involving the kidney but cysts can also occur in other organs such as the liver, pancreas, arachnoid membrane and seminal vesicles. Though computed tomography and magnetic resonance imaging (MRI) were similar in evaluating 81% of cystic lesions of the kidney, MRI may depict septa, wall thickening or enhancement leading to upgrade in cyst classification that can affect management. A screening strategy for intracranial aneurysms would provide 1.0 additional year of life without neurological disability to a 20-year-old patient with ADPKD and reduce the financial impact on society of the disease. Current treatment strategies include reducing: cyclic adenosine monophosphate levels, cell proliferation and fluid secretion. Several randomised clinical trials (RCT) including mammalian target of rapamycin inhibitors, somatostatin analogues and a vasopressin V2 receptor antagonist have been performed to study the effect of diverse drugs on growth of renal and hepatic cysts, and on deterioration of renal function. Prophylactic native nephrectomy is indicated in patients with a history of cyst infection or recurrent haemorrhage or to those in whom space must be made to implant the graft. The absence of large RCT on various aspects of the disease and its treatment leaves considerable uncertainty and ambiguity in many aspects of ADPKD patient care as it relates to end stage renal disease (ESRD). The outlook of patients with ADPKD is improving and is in fact much better than that for patients in ESRD due to other causes. This review highlights the need for well-structured RCTs as a first step towards trying newer interventions so as to develop updated clinical management guidelines.
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32
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Fcγ and Complement Receptors and Complement Proteins in Neutrophil Activation in Rheumatoid Arthritis: Contribution to Pathogenesis and Progression and Modulation by Natural Products. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2015; 2015:429878. [PMID: 26346244 PMCID: PMC4540990 DOI: 10.1155/2015/429878] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Academic Contribution Register] [Received: 04/01/2015] [Revised: 06/30/2015] [Accepted: 07/05/2015] [Indexed: 12/29/2022]
Abstract
Rheumatoid arthritis (RA) is a highly disabling disease that affects all structures of the joint and significantly impacts on morbidity and mortality in RA patients. RA is characterized by persistent inflammation of the synovial membrane lining the joint associated with infiltration of immune cells. Eighty to 90% of the leukocytes infiltrating the synovia are neutrophils. The specific role that neutrophils play in the onset of RA is not clear, but recent studies have evidenced that they have an important participation in joint damage and disease progression through the release of proteolytic enzymes, reactive oxygen species (ROS), cytokines, and neutrophil extracellular traps, in particular during frustrated phagocytosis of immune complexes (ICs). In addition, the local and systemic activation of the complement system contributes to the pathogenesis of RA and other IC-mediated diseases. This review discusses (i) the participation of Fcγ and complement receptors in mediating the effector functions of neutrophils in RA; (ii) the contribution of the complement system and ROS-dependent and ROS-independent mechanisms to joint damage in RA; and (iii) the use of plant extracts, dietary compounds, and isolated natural compounds in the treatment of RA, focusing on modulation of the effector functions of neutrophils and the complement system activity and/or activation.
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33
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Fearn A, Sheerin NS. Complement activation in progressive renal disease. World J Nephrol 2015; 4:31-40. [PMID: 25664245 PMCID: PMC4317626 DOI: 10.5527/wjn.v4.i1.31] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 09/02/2014] [Revised: 11/14/2014] [Accepted: 12/10/2014] [Indexed: 02/06/2023] Open
Abstract
Chronic kidney disease (CKD) is common and the cause of significant morbidity and mortality. The replacement of functioning nephrons by fibrosis is characteristic of progressive disease. The pathways that lead to fibrosis are not fully understood, although chronic non-resolving inflammation in the kidney is likely to drive the fibrotic response that occurs. In patients with progressive CKD there is histological evidence of inflammation in the interstitium and strategies that reduce inflammation reduce renal injury in pre-clinical models of CKD. The complement system is an integral part of the innate immune system but also augments adaptive immune responses. Complement activation is known to occur in many diverse renal diseases, including glomerulonephritis, thrombotic microangiopathies and transplant rejection. In this review we discuss current evidence that complement activation contributes to progression of CKD, how complement could cause renal inflammation and whether complement inhibition would slow progression of renal disease.
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34
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Bauer A, Limperger V, Nowak-Göttl U. End-stage renal disease and thrombophilia. Hamostaseologie 2015; 36:103-7. [PMID: 25639843 DOI: 10.5482/hamo-14-11-0063] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/13/2014] [Accepted: 01/23/2015] [Indexed: 11/05/2022] Open
Abstract
Chronic kidney disease is an established risk factor for arterial and venous thromboembolism (TE). Whereas the overall risk of TE in moderately decreased kidney function is approximately 2.5-fold higher compared to patients with normal renal function, the risk increase is 5.5-fold in patients with severe renal dysfunction. In patients with renal dysfunction and arterial thrombosis (OR: 4.9), malignancy (OR: 5.8) surgery (OR: 14.0) or thrombophilia (OR: 4.3) the risk to suffer from venous TE is higher compared to the risk associated to the baseline renal dysfunction alone. The treatment options for end-stage renal diseases include hemodialysis, peritoneal dialysis and kidney transplantation. During all treatment modalities thrombotic complications have been described, namely catheter malfunction and shunt thrombosis in patients undergoing hemodialysis in up to 25% of patients, and TE, pulmonary embolism or graft vessel thrombosis in approximately 8% of patients. The reported incidence of reno-vascular thrombosis following renal transplantation leading to hemorrhagic infarction with organ rejection or organ loss varied between 2-12%. Keeping in mind the multifactorial etiology of TE in patients with kidney dysfunction a general screening for thrombophilia in this patient group is not indicated. Selected screening on an individual patient basis should be discussed if the family history for TE is positive or the patient itself had suffered one thrombosis before the onset of the renal disease or multiple TEs during hemodialysis or post kidney transplantation in patients waiting for living donor kidney transplantation.
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Affiliation(s)
| | | | - Ulrike Nowak-Göttl
- Prof. Dr. Ulrike Nowak-Göttl, Institute of Clinical Chemistry, Thrombosis & Hemostasis Treatment Center, Univ. Hospital Schleswig Holstein, Campus Kiel & Lübeck, Arnold-Heller-Str. 5, 24105 Kiel, E-mail:
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35
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Danobeitia JS, Djamali A, Fernandez LA. The role of complement in the pathogenesis of renal ischemia-reperfusion injury and fibrosis. FIBROGENESIS & TISSUE REPAIR 2014. [PMID: 25383094 DOI: 10.1186/1755‐1536‐7‐16] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Academic Contribution Register] [Indexed: 01/04/2023]
Abstract
The complement system is a major component of innate immunity and has been commonly identified as a central element in host defense, clearance of immune complexes, and tissue homeostasis. After ischemia-reperfusion injury (IRI), the complement system is activated by endogenous ligands that trigger proteolytic cleavage of complement components via the classical, lectin and/or alternative pathway. The result is the formation of terminal complement components C3a, C5a, and the membrane attack complex (C5b-9 or MAC), all of which play pivotal roles in the amplification of the inflammatory response, chemotaxis, neutrophil/monocyte recruitment and activation, and direct tubular cell injury. However, recent evidence suggests that complement activity transcends innate host defense and there is increasing data suggesting complement as a regulator in processes such as allo-immunity, stem cell differentiation, tissue repair, and progression to fibrosis. In this review, we discuss recent advances addressing the role of complement as a regulator of IRI and renal fibrosis after organ donation for transplantation. We will also briefly discuss currently approved therapies that target complement activity in kidney ischemia-reperfusion and transplantation.
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Affiliation(s)
- Juan S Danobeitia
- Department of Surgery, Division of Transplantation, University of Wisconsin-Madison School of Medicine and Public Health, H4/782 Clinical Science Center, 600 Highland Avenue, 53792 Madison, WI, USA
| | - Arjang Djamali
- Department of Medicine, Division of Nephrology, University of Wisconsin- Madison School of Medicine and Public Health, UW Medical Foundation Centennial Building, 1685 Highland Avenue, 53705 Madison, WI, USA
| | - Luis A Fernandez
- Department of Surgery, Division of Transplantation, University of Wisconsin-Madison School of Medicine and Public Health, H4/782 Clinical Science Center, 600 Highland Avenue, 53792 Madison, WI, USA
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36
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Su Z, Wüthrich RP, Mei C. Response to letter from the editor 'Complement C3 activation in cyst fluid and urine from autosomal dominant polycystic kidney disease patients'. J Intern Med 2014; 276:541-2. [PMID: 25205431 DOI: 10.1111/joim.12306] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 11/29/2022]
Affiliation(s)
- Z Su
- Department of Nephrology, Shanghai Changzheng Hospital, Kidney Institute, Second Military Medical University, Shanghai, China
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37
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Danobeitia JS, Djamali A, Fernandez LA. The role of complement in the pathogenesis of renal ischemia-reperfusion injury and fibrosis. FIBROGENESIS & TISSUE REPAIR 2014; 7:16. [PMID: 25383094 PMCID: PMC4224961 DOI: 10.1186/1755-1536-7-16] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Academic Contribution Register] [Received: 06/22/2014] [Accepted: 09/17/2014] [Indexed: 01/04/2023]
Abstract
The complement system is a major component of innate immunity and has been commonly identified as a central element in host defense, clearance of immune complexes, and tissue homeostasis. After ischemia-reperfusion injury (IRI), the complement system is activated by endogenous ligands that trigger proteolytic cleavage of complement components via the classical, lectin and/or alternative pathway. The result is the formation of terminal complement components C3a, C5a, and the membrane attack complex (C5b-9 or MAC), all of which play pivotal roles in the amplification of the inflammatory response, chemotaxis, neutrophil/monocyte recruitment and activation, and direct tubular cell injury. However, recent evidence suggests that complement activity transcends innate host defense and there is increasing data suggesting complement as a regulator in processes such as allo-immunity, stem cell differentiation, tissue repair, and progression to fibrosis. In this review, we discuss recent advances addressing the role of complement as a regulator of IRI and renal fibrosis after organ donation for transplantation. We will also briefly discuss currently approved therapies that target complement activity in kidney ischemia-reperfusion and transplantation.
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Affiliation(s)
- Juan S Danobeitia
- Department of Surgery, Division of Transplantation, University of Wisconsin-Madison School of Medicine and Public Health, H4/782 Clinical Science Center, 600 Highland Avenue, 53792 Madison, WI, USA
| | - Arjang Djamali
- Department of Medicine, Division of Nephrology, University of Wisconsin- Madison School of Medicine and Public Health, UW Medical Foundation Centennial Building, 1685 Highland Avenue, 53705 Madison, WI, USA
| | - Luis A Fernandez
- Department of Surgery, Division of Transplantation, University of Wisconsin-Madison School of Medicine and Public Health, H4/782 Clinical Science Center, 600 Highland Avenue, 53792 Madison, WI, USA
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Mrug M, Zhou J, Mrug S, Guay-Woodford LM, Yoder BK, Szalai AJ. Complement C3 activation in cyst fluid and urine from autosomal dominant polycystic kidney disease patients. J Intern Med 2014; 276:539-40. [PMID: 25205519 DOI: 10.1111/joim.12307] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 11/28/2022]
Affiliation(s)
- M Mrug
- Division of Nephrology, Nephrology Research and Training Center, University of Alabama at Birmingham, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Veterans Affairs Medical Center, University of Alabama at Birmingham, Birmingham, AL, USA
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