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Jana S, Mitra P, Dutta A, Khatun A, Kumar Das T, Pradhan S, Kumar Nandi D, Roy S. Early diagnostic biomarkers for acute kidney injury using cisplatin-induced nephrotoxicity in rat model. Curr Res Toxicol 2023; 5:100135. [PMID: 38033659 PMCID: PMC10682538 DOI: 10.1016/j.crtox.2023.100135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 11/01/2023] [Accepted: 11/06/2023] [Indexed: 12/02/2023] Open
Abstract
Chronic kidney diseases (CKD) caused by acute kidney injury (AKI) results rapid and reversible loss in renal function. A real-time, highly accurate, and sensitive acute kidney injury biomarker is urgently required in order to keep these patients alive and prevent end stage renal disease and related complications that include hypertension, fluid and electrolyte retention, metabolic acidosis, anemia, stroke etc. This study was designed to develop a specific and sensitive model for the early identification of renal damage in male albino rats. Using a single intraperitoneal dose of cisplatin (10 mg/kg body weight) to the rats, the various duration-dependent nephrotoxic activities were compared using multiple physiological, biochemical, genomic, and histopathological markers. We looked into when renal dysfunction would start occurring after receiving a single high dose of cisplatin while blood urea nitrogen (BUN) and serum creatinine (sCr) remained normal. Following a single cisplatin injection, various measurements were taken in plasma, urine, and/or kidney tissues of rats euthanized on days 1, 2, 3, 5, and 7. When the urine kidney injury molecule (KIM-1), interleukine 18 (IL-18), nephrin, neutrophil gelatinase-associated lipocalin (NGAL) and serum cystatin C (Cys C) levels are greatly raised on day 3 after cisplatin treatment, BUN and sCr levels remain normal. Nephrotoxicity of cisplatin is also indicated by the upregulated mRNA expression of KIM-1, IL-18, Cys C, and NGAL and downregulated expression of nephrin in kidney tissue at very initial stage. Protein expression of KIM-1, IL-18 and NGAL level of kidney tissues was upregulated indicated confirmatory results done by western blot. Utilising an array of kidney impairment indicators has emerged as an earlier, more effective, and more reliable technique to diagnose AKI when compared to the most sophisticated signs now available.
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Affiliation(s)
- Sahadeb Jana
- Biodiversity and Environmental Studies Research Center, Midnapore City College, Kuturiya, Bhadutala, Midnapore, Paschim Medinipur, Pin- 721129, West Bengal, India
- Nutrition Research Laboratory, Department of Paramedical and Allied Health Sciences, Midnapore City College, Midnapore, Paschim Medinipur, Pin-721129, West Bengal, India
| | - Palash Mitra
- Nutrition Research Laboratory, Department of Paramedical and Allied Health Sciences, Midnapore City College, Midnapore, Paschim Medinipur, Pin-721129, West Bengal, India
| | - Ananya Dutta
- Biodiversity and Environmental Studies Research Center, Midnapore City College, Kuturiya, Bhadutala, Midnapore, Paschim Medinipur, Pin- 721129, West Bengal, India
- Nutrition Research Laboratory, Department of Paramedical and Allied Health Sciences, Midnapore City College, Midnapore, Paschim Medinipur, Pin-721129, West Bengal, India
| | - Amina Khatun
- Biodiversity and Environmental Studies Research Center, Midnapore City College, Kuturiya, Bhadutala, Midnapore, Paschim Medinipur, Pin- 721129, West Bengal, India
- Nutrition Research Laboratory, Department of Paramedical and Allied Health Sciences, Midnapore City College, Midnapore, Paschim Medinipur, Pin-721129, West Bengal, India
| | - Tridip Kumar Das
- Biodiversity and Environmental Studies Research Center, Midnapore City College, Kuturiya, Bhadutala, Midnapore, Paschim Medinipur, Pin- 721129, West Bengal, India
- Nutrition Research Laboratory, Department of Paramedical and Allied Health Sciences, Midnapore City College, Midnapore, Paschim Medinipur, Pin-721129, West Bengal, India
| | - Shrabani Pradhan
- Nutrition Research Laboratory, Department of Paramedical and Allied Health Sciences, Midnapore City College, Midnapore, Paschim Medinipur, Pin-721129, West Bengal, India
| | - Dilip Kumar Nandi
- Nutrition Research Laboratory, Department of Paramedical and Allied Health Sciences, Midnapore City College, Midnapore, Paschim Medinipur, Pin-721129, West Bengal, India
| | - Suchismita Roy
- Nutrition Research Laboratory, Department of Paramedical and Allied Health Sciences, Midnapore City College, Midnapore, Paschim Medinipur, Pin-721129, West Bengal, India
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Zhang Y, Chen P, Wang B, Tang X, Wei Y, Cao W, Tang L, Wang Z, Zhao N. Containing anti-PLA2R IgG antibody induces podocyte injury in idiopathic membranous nephropathy. Ren Fail 2023; 45:2271986. [PMID: 37905942 PMCID: PMC11001355 DOI: 10.1080/0886022x.2023.2271986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 10/12/2023] [Indexed: 11/02/2023] Open
Abstract
Background: Idiopathic membranous nephropathy is widely recognized as an autoimmune kidney disease that is accompanied by the discovery of several autoantibodies, and the antibody subclass in the circulation of patients with iMN is mainly IgG. However, the direct pathogenic effect of the containing anti-PLA2R IgG antibody on podocytes is not clear.Method: A protein G affinity chromatography column was used to purify serum IgG antibodies. Containing anti-PLA2R IgG antibodies from iMN patients and IgG from healthy controls were also obtained. Based on the established in vitro podocyte culture system, purified IgG antibodies from the two groups were used to stimulate podocytes, and the expression of essential podocyte proteins (podocin), the levels of inflammatory cytokines in the cell supernatant, cytoskeletal disorders, and podocyte apoptosis were analyzed.Results: Compared with that in the normal IgG group, the expression of podocin and podocin mRNA was reduced (p = 0.016 and p = 0.005, respectively), the fluorescence intensity of podocin on the surface of podocytes was reduced, the cytoskeleton of podocytes was disordered and reorganized, and the ratio of podocyte apoptosis was increased in the iMN group (p = 0.008).Conclusion: The containing anti-PLA2R IgG antibody might have a direct damaging effect on podocytes in idiopathic membranous nephropathy.
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Affiliation(s)
- Ying Zhang
- Department of Nephrology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
- Shandong Provincial Key Laboratory for Rheumatic Disease and Translational Medicine, Jinan, China
- Nephrology Research Institute of Shandong Province, Jinan, China
| | - Ping Chen
- Department of Nephrology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
- Shandong Provincial Key Laboratory for Rheumatic Disease and Translational Medicine, Jinan, China
- Nephrology Research Institute of Shandong Province, Jinan, China
| | - Baobao Wang
- Department of Nephrology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
- Shandong Provincial Key Laboratory for Rheumatic Disease and Translational Medicine, Jinan, China
- Nephrology Research Institute of Shandong Province, Jinan, China
| | - Xueqing Tang
- Department of Nephrology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
- Shandong Provincial Key Laboratory for Rheumatic Disease and Translational Medicine, Jinan, China
- Nephrology Research Institute of Shandong Province, Jinan, China
| | - Yong Wei
- Department of Nephrology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
- Shandong Provincial Key Laboratory for Rheumatic Disease and Translational Medicine, Jinan, China
- Nephrology Research Institute of Shandong Province, Jinan, China
| | - Wei Cao
- Department of Nephrology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
- Shandong Provincial Key Laboratory for Rheumatic Disease and Translational Medicine, Jinan, China
- Nephrology Research Institute of Shandong Province, Jinan, China
| | - Lijun Tang
- Department of Nephrology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
- Shandong Provincial Key Laboratory for Rheumatic Disease and Translational Medicine, Jinan, China
- Nephrology Research Institute of Shandong Province, Jinan, China
| | - Zunsong Wang
- Department of Nephrology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
- Shandong Provincial Key Laboratory for Rheumatic Disease and Translational Medicine, Jinan, China
- Nephrology Research Institute of Shandong Province, Jinan, China
| | - Na Zhao
- Department of Nephrology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
- Shandong Provincial Key Laboratory for Rheumatic Disease and Translational Medicine, Jinan, China
- Nephrology Research Institute of Shandong Province, Jinan, China
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Grubczak K, Starosz A, Makowska B, Parfienowicz Z, Krętowska M, Naumnik B, Moniuszko M. The influence of calcitriol and methylprednisolone on podocytes function in minimal change disease in vitro model. Sci Rep 2023; 13:12731. [PMID: 37543700 PMCID: PMC10404287 DOI: 10.1038/s41598-023-39893-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Accepted: 08/01/2023] [Indexed: 08/07/2023] Open
Abstract
Minimal change disease (MCD), considered one of the major causes of nephrotic syndrome, is a complex pathological condition with disturbances in podocytes' foot processes. Numerous studies suggested the essential role of vitamin D3 in maintaining proper glomerulus function. However, the data on direct potential of that compound in reference to podocytes are scarce. Thus, here we assessed the influence of calcitriol (active vitamin D3) on podocyte function, apart from commonly used steroids (methylprednisolone). CIHP-1 podocyte cell line was used to implement the LPS-PAN-induced MCD in vitro model. Viability, podocyte-related slit diaphragm proteins, morphology, function as a barrier was evaluated using flow cytometry, RT-PCR, confocal microscopy, and TEER analysis. Calcitriol or methylprednisolone did not affect cell viability. Podocyte-related proteins demonstrated different responses to in vitro treatment compared to previously reported changes in total glomeruli. Podocyte morphology was partially restored in the presence of the tested compounds. In addition, TEER analysis revealed improvement of LPS-PAN-induced cells' function as a barrier when vitamin D3 or steroid was used. In conclusion, a significant potential for modulation of MCD in vitro model podocytes with calcitriol or selected steroids was reported. Further studies on vitamin D3 in context of podocyte-related phenomenon accompanying MCD are of great importance.
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Affiliation(s)
- Kamil Grubczak
- Department of Regenerative Medicine and Immune Regulation, Medical University of Białystok, Jerzego Waszyngtona 13, 15-269, Białystok, Poland.
| | - Aleksandra Starosz
- Department of Regenerative Medicine and Immune Regulation, Medical University of Białystok, Jerzego Waszyngtona 13, 15-269, Białystok, Poland
| | - Barbara Makowska
- Department of Regenerative Medicine and Immune Regulation, Medical University of Białystok, Jerzego Waszyngtona 13, 15-269, Białystok, Poland
| | - Zuzanna Parfienowicz
- Department of Regenerative Medicine and Immune Regulation, Medical University of Białystok, Jerzego Waszyngtona 13, 15-269, Białystok, Poland
| | - Magdalena Krętowska
- Department of Regenerative Medicine and Immune Regulation, Medical University of Białystok, Jerzego Waszyngtona 13, 15-269, Białystok, Poland
| | - Beata Naumnik
- Ist Department of Nephrology and Transplantation with Dialysis Unit, Medical University of Bialystok, Żurawia 14, 15-540, Białystok, Poland.
| | - Marcin Moniuszko
- Department of Regenerative Medicine and Immune Regulation, Medical University of Białystok, Jerzego Waszyngtona 13, 15-269, Białystok, Poland
- Department of Allergology and Internal Medicine, Medical University of Białystok, Marii Skłodowskiej-Curie 24A, 15-276, Białystok, Poland
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Hu QD, Tan RZ, Zou YX, Li JC, Fan JM, Kantawong F, Wang L. Synergism of calycosin and bone marrow-derived mesenchymal stem cells to combat podocyte apoptosis to alleviate adriamycin-induced focal segmental glomerulosclerosis. World J Stem Cells 2023; 15:617-631. [PMID: 37424951 PMCID: PMC10324505 DOI: 10.4252/wjsc.v15.i6.617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 04/28/2023] [Accepted: 05/25/2023] [Indexed: 06/26/2023] Open
Abstract
BACKGROUND Bone marrow-derived mesenchymal stem cells (MSCs) show podocyte-protective effects in chronic kidney disease. Calycosin (CA), a phytoestrogen, is isolated from Astragalus membranaceus with a kidney-tonifying effect. CA preconditioning enhances the protective effect of MSCs against renal fibrosis in mice with unilateral ureteral occlusion. However, the protective effect and underlying mechanism of CA-pretreated MSCs (MSCsCA) on podocytes in adriamycin (ADR)-induced focal segmental glomerulosclerosis (FSGS) mice remain unclear. AIM To investigate whether CA enhances the role of MSCs in protecting against podocyte injury induced by ADR and the possible mechanism involved. METHODS ADR was used to induce FSGS in mice, and MSCs, CA, or MSCsCA were administered to mice. Their protective effect and possible mechanism of action on podocytes were observed by Western blot, immunohistochemistry, immunofluorescence, and real-time polymerase chain reaction. In vitro, ADR was used to stimulate mouse podocytes (MPC5) to induce injury, and the supernatants from MSC-, CA-, or MSCsCA-treated cells were collected to observe their protective effects on podocytes. Subsequently, the apoptosis of podocytes was detected in vivo and in vitro by Western blot, TUNEL assay, and immunofluorescence. Overexpression of Smad3, which is involved in apoptosis, was then induced to evaluate whether the MSCsCA-mediated podocyte protective effect is associated with Smad3 inhibition in MPC5 cells. RESULTS CA-pretreated MSCs enhanced the protective effect of MSCs against podocyte injury and the ability to inhibit podocyte apoptosis in ADR-induced FSGS mice and MPC5 cells. Expression of p-Smad3 was upregulated in mice with ADR-induced FSGS and MPC5 cells, which was reversed by MSCCA treatment more significantly than by MSCs or CA alone. When Smad3 was overexpressed in MPC5 cells, MSCsCA could not fulfill their potential to inhibit podocyte apoptosis. CONCLUSION MSCsCA enhance the protection of MSCs against ADR-induced podocyte apoptosis. The underlying mechanism may be related to MSCsCA-targeted inhibition of p-Smad3 in podocytes.
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Affiliation(s)
- Qiong-Dan Hu
- Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand
- Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou 646000, Sichuan Province, China
- Department of Nephrology, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou 646000, Sichuan Province, China
| | - Rui-Zhi Tan
- Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand
- Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou 646000, Sichuan Province, China
| | - Yuan-Xia Zou
- Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou 646000, Sichuan Province, China
- Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Jian-Chun Li
- Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou 646000, Sichuan Province, China
- Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Jun-Ming Fan
- Department of Nephrology, The Affiliated Hospital of Chengdu Medical College, Chengdu 610500, Sichuan Province, China
| | - Fahsai Kantawong
- Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Li Wang
- Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou 646000, Sichuan Province, China.
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El-Far AH, Lebda MA, Noreldin AE, Atta MS, Elewa YHA, Elfeky M, Mousa SA. Quercetin Attenuates Pancreatic and Renal D-Galactose-Induced Aging-Related Oxidative Alterations in Rats. Int J Mol Sci 2020; 21:E4348. [PMID: 32570962 PMCID: PMC7352460 DOI: 10.3390/ijms21124348] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 06/11/2020] [Accepted: 06/15/2020] [Indexed: 02/07/2023] Open
Abstract
Aging is an oxidative stress-associated process that progresses with age. Our aim is to delay or attenuate these oxidative alterations and to keep individuals healthy as they age using natural compounds supplementation. Therefore, we conducted the present study to investigate the protective potentials of quercetin against D-galactose (D-gal)-associated oxidative alterations that were induced experimentally in male Wistar rats. Forty-five rats were randomly allocated into five groups of nine rats each. The groups were a control group that was reared on a basal diet and injected subcutaneously with 120 mg D-gal dissolved in physiological saline solution (0.9% NaCl) per kg body weight daily and quercetin-treated groups that received the same basal diet and subcutaneous daily D-gal injections were supplemented orally with 25, 50, and 100 mg of quercetin per kg body weight for 42 days. Pancreatic and renal samples were subjected to histopathological, immunohistochemical, and relative mRNA expression assessments. Aging (p53, p21, IL-6, and IL-8), apoptotic (Bax, CASP-3, and caspase-3 protein), proliferative (Ki67 protein), antiapoptotic (Bcl2 and Bcl2 protein), inflammatory (NF-κB, IL-1β, and TNF-α), antioxidant (SOD1), and functional markers (GCLC and GCLM genes and insulin, glucagon, and podocin proteins) were determined to evaluate the oxidative alterations induced by D-gal and the protective role of quercetin. D-gal caused oxidative alterations of the pancreas and kidneys observed via upregulations of aging, apoptotic, and inflammatory markers and downregulated the antiapoptotic, proliferative, antioxidant, and functional markers. Quercetin potentially attenuated these aging-related oxidative alterations in a dose-dependent manner. Finally, we can conclude that quercetin supplementation is considered as a promising natural protective compound that could be used to delay the aging process and to maintain human health.
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Affiliation(s)
- Ali H. El-Far
- Department of Biochemistry, Faculty of Veterinary Medicine, Damanhour University, Damanhour 22511, Egypt
| | - Mohamed A. Lebda
- Biochemistry Department, Faculty of Veterinary Medicine, Alexandria University, Alexandria 22758, Egypt; (M.A.L.); (M.E.)
| | - Ahmed E. Noreldin
- Histology and Cytology Department, Faculty of Veterinary Medicine, Damanhour University, Damanhour 22511, Egypt;
| | - Mustafa S. Atta
- Department of Physiology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh 33516, Egypt;
| | - Yaser H. A. Elewa
- Histology and Cytology Department, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, Egypt;
- Laboratory of Anatomy, Faculty of Veterinary Medicine, Basic Veterinary Sciences, Hokkaido University, Sapporo 060-0818, Japan
| | - Mohamed Elfeky
- Biochemistry Department, Faculty of Veterinary Medicine, Alexandria University, Alexandria 22758, Egypt; (M.A.L.); (M.E.)
| | - Shaker A. Mousa
- Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY 12144, USA
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Bąchor R, Gąszczyk D, Panek-Laszczyńska K, Konieczny A, Witkiewicz W, Stefanowicz P, Szewczuk Z. Detection of Podocin in Human Urine Sediment Samples by Charge Derivatization and LC-MS-MRM Method. Int J Mol Sci 2020; 21:ijms21093225. [PMID: 32370166 PMCID: PMC7247335 DOI: 10.3390/ijms21093225] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 04/20/2020] [Accepted: 04/30/2020] [Indexed: 12/14/2022] Open
Abstract
Detection of podocytes in urine might serve as a useful diagnostic tool in both primary and secondary glomerular diseases. The utility of podocyturia has been confirmed for both pre-eclampsia and glomerulonephritis. Here, we present a new and sensitive method for qualitative LC-MS-multiple-reaction-monitoring (MRM) analysis of podocin, serving as a podocyturia biomarker in urine sediments. The following podocin tryptic peptides with the 169LQTLEIPFHEIVTK182, 213AVQFLVQTTMK223, 240SIAQDAK246, and 292MIAAEAEK299 sequences were applied as a model. The selective chemical derivatization of the ε amino group of C-terminal lysine residue in tryptic peptides, by 2,4,6-triphenylpyrylium salt (TPP) as a fixed charge tag, was employed to increase the ionization efficiency, in routine ESI-MS analysis. Additionally, the generation of a reporter ion, in the form of a protonated 2,4,6-triphenylpyridinium cation, makes the derivatized peptide analysis in the MRM mode unambiguous. Identification of derivatized and non-derivatized peptides were performed, and the obtained results suggest that the peptide with the 292MIAAEAEK299 sequence may serve as a marker of podocyturia.
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Affiliation(s)
- Remigiusz Bąchor
- Faculty of Chemistry, University of Wroclaw, 50-383 Wroclaw, Poland; (D.G.); (P.S.); (Z.S.)
- Correspondence: ; Tel.: +48-71-375-7218; Fax: +48-71-328-2348
| | - Dorota Gąszczyk
- Faculty of Chemistry, University of Wroclaw, 50-383 Wroclaw, Poland; (D.G.); (P.S.); (Z.S.)
| | - Karolina Panek-Laszczyńska
- 1st Department and Clinic of Gynecology and Obstetrics, Wroclaw Medical University, 50-368 Wroclaw, Poland;
| | - Andrzej Konieczny
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, 50-556 Wroclaw, Poland;
| | - Wojciech Witkiewicz
- Research and Development Center, Regional Specialized Hospital, 51-124 Wroclaw, Poland;
| | - Piotr Stefanowicz
- Faculty of Chemistry, University of Wroclaw, 50-383 Wroclaw, Poland; (D.G.); (P.S.); (Z.S.)
| | - Zbigniew Szewczuk
- Faculty of Chemistry, University of Wroclaw, 50-383 Wroclaw, Poland; (D.G.); (P.S.); (Z.S.)
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Hao GX, Song LL, Zhang DF, Su LQ, Jacqz-Aigrain E, Zhao W. Off-label use of tacrolimus in children with glomerular disease: Effectiveness, safety and pharmacokinetics. Br J Clin Pharmacol 2020; 86:274-284. [PMID: 31725919 DOI: 10.1111/bcp.14174] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 10/21/2019] [Accepted: 11/04/2019] [Indexed: 12/13/2022] Open
Abstract
Glomerular diseases are leading causes of end-stage renal disease in children. Tacrolimus is frequently used off-label in the treatment of glomerular diseases. The effectiveness, safety and pharmacokinetic data of tacrolimus in the treatment of glomerular diseases in children are reviewed in this paper to provide evidence to support its rational use in clinical practice. The remission rates in previously published studies were different. In 19 clinical trials on children with nephrotic syndrome, the overall remission rate was 52.6-97.6%. In four clinical trials on children with lupus nephritis, the overall remission rate was 81.8-89.5%. In a pilot study with paediatric Henoch-Schönlein purpura nephritis patients, the overall remission rate was 100.0%. Infection, nephrotoxicity, gastrointestinal symptoms and hypertension are the most common adverse events. Body weight, age, CYP3A5 genotype, cystatin-C and daily dose of tacrolimus may have significant effects on the pharmacokinetics of tacrolimus in children with glomerular disease. More prospective controlled trials with long follow-up are needed to demonstrate definitely the effectiveness, safety and pharmacokinetics of tacrolimus in children with glomerular diseases.
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Affiliation(s)
- Guo-Xiang Hao
- Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Lin-Lin Song
- Department of Pharmacy, Shandong Provincial Qianfoshan Hospital, the First Hospital Affiliated with Shandong First Medical University, Jinan, China
| | - Dong-Feng Zhang
- Department of Pediatric Nephrology, Children's Hospital of Hebei Province affiliated to Hebei Medical University, Shijiazhuang, China
| | - Le-Qun Su
- Department of Pharmacy, Shandong Provincial Qianfoshan Hospital, the First Hospital Affiliated with Shandong First Medical University, Jinan, China
| | - Evelyne Jacqz-Aigrain
- Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, APHP, Paris, France
| | - Wei Zhao
- Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University, Jinan, China.,Department of Pharmacy, Shandong Provincial Qianfoshan Hospital, the First Hospital Affiliated with Shandong First Medical University, Jinan, China
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8
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Eroglu FK, Orhan D, İnözü M, Duzova A, Gulhan B, Ozaltin F, Topaloglu R. CD80 expression and infiltrating regulatory T cells in idiopathic nephrotic syndrome of childhood. Pediatr Int 2019; 61:1250-1256. [PMID: 31513327 DOI: 10.1111/ped.14005] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 07/05/2019] [Accepted: 09/06/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND CD80 (also known as B7-1) is a co-stimulatory molecule that is expressed in biopsies and also excreted in urine in patients with minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). CD80 is inhibited by the cytotoxic T-lymphocyte-associated-antigen 4 (CTLA4), which is mainly expressed on regulatory T cells (Tregs). Ineffective circulating Treg response is involved in the pathogenesis of nephrotic syndrome. In this study, we evaluated CD80 expression and infiltrating Tregs in children with MCD and FSGS. METHODS Evaluation of CD80 expression and semi-quantitative evaluation of Tregs (FOXP3-positive CD4 T cells) were carried out in 31 kidney biopsies (12 MCD, 19 FSGS) with immunofluorescence and immunohistochemistry staining. RESULTS All MCD sections were stained negative; whereas six out of 19 FSGS sections (all from steroid-resistant (SR) patients), including one from a Wilms' tumor 1 (WT1) mutation-positive FSGS patient, stained positive for anti-CD80 goat antibody, and negative for anti-CD80 rabbit antibody. FSGS biopsy specimens had significantly higher FOXP3-positive cells/mm2 compared with MCD and control samples (P < 0.001). Biopsy samples from SR-FSGS patients (n = 12) with positive CD80 staining (n = 6) had significantly less Tregs (FOXP3-positive CD4 T cells) compared with CD80 (-) biopsies (n = 6; P = 0.004). CONCLUSION CD80 expression was not detected in the majority of the archival biopsy sections and the results were not consistent across the different antibodies. In the SR-FSGS sections, however, CD80-positive biopsies had decreased FOXP3-positive CD4 T cells, suggesting that a decreased anti-inflammatory milieu may be the cause of increased CD80 expression.
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Affiliation(s)
- Fehime Kara Eroglu
- Division of Pediatric Nephrology, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Diclehan Orhan
- Department of Pathology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Mihriban İnözü
- Division of Pediatric Nephrology, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Ali Duzova
- Division of Pediatric Nephrology, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Bora Gulhan
- Division of Pediatric Nephrology, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Fatih Ozaltin
- Division of Pediatric Nephrology, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Rezan Topaloglu
- Division of Pediatric Nephrology, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey
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9
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Pereira LHDM, da Silva CA, Monteiro MLGDR, Araújo LS, Rocha LP, Reis MBDR, Ramalho FS, Corrêa RRM, Silva MV, Reis MA, Machado JR. Podocin and uPAR are good biomarkers in cases of Focal and segmental glomerulosclerosis in pediatric renal biopsies. PLoS One 2019; 14:e0217569. [PMID: 31188898 PMCID: PMC6561567 DOI: 10.1371/journal.pone.0217569] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Accepted: 05/14/2019] [Indexed: 01/10/2023] Open
Abstract
There are controversies whether Minimal Change Disease (MCD) and Focal and Segmental Glomerulosclerosis (FSGS) are distinct glomerular lesions or different manifestations within the same spectrum of diseases. The uPAR (urokinase-type plasminogen activator receptor) and some slit diaphragm proteins may be altered in FSGS glomeruli and may function as biomarkers of the disease in renal biopsies. Thus, this study aims to evaluate the diagnostic potential of uPAR and glomerular proteins for differentiation between MCD and FSGS in renal pediatric biopsy. Renal biopsies from 50 children between 2 and 18 years old were selected, with diagnosis of MCD (n = 29) and FSGS (n = 21). Control group consisted of pediatric autopsies (n = 15) from patients younger than 18 years old, with no evidences of renal dysfunction. In situ expressions of WT1, nephrin, podocin and uPAR were evaluated by immunoperoxidase technique. Renal biopsy of patients with MCD and FSGS expressed fewer WT1 (p≤0.0001, F = 19.35) and nephrin (p<0.0001; H = 21.54) than patients in the control group. FSGS patients expressed fewer podocin than control (p<0.0359, H = 6.655). FSGS cases expressed more uPAR than each of control and MCD (p = 0.0019; H = 12.57) and there was a positive and significant correlation between nephrin and podocin (p = 0.0026, rS = 0.6502) in these cases. Podocin had sensitivity of 73.3% and specificity of 86.7% (p = 0.0068) and uPAR had sensitivity of 78.9% and specificity of 73.3% (p = 0.0040) for diagnosis of FSGS patients. The main limitation of the study is the limited number of cases due to the difficulty in performing biopsy in pediatric patients. Podocin and uPAR are good markers for FSGS and differentiate these cases from MCD, reinforcing the theory of distinct glomerular diseases. These findings suggest that podocin and uPAR can be used as biomarkers in the routine analysis of renal biopsies in cases of podocytopathies when the lesion (sclerosis) is not sampled.
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MESH Headings
- Adolescent
- Autopsy
- Biomarkers/metabolism
- Biopsy
- Case-Control Studies
- Child
- Child, Preschool
- Diagnosis, Differential
- Female
- Gene Expression
- Glomerulosclerosis, Focal Segmental/diagnosis
- Glomerulosclerosis, Focal Segmental/genetics
- Glomerulosclerosis, Focal Segmental/metabolism
- Glomerulosclerosis, Focal Segmental/pathology
- Humans
- Intracellular Signaling Peptides and Proteins/genetics
- Intracellular Signaling Peptides and Proteins/metabolism
- Kidney Glomerulus/metabolism
- Kidney Glomerulus/pathology
- Male
- Membrane Proteins/genetics
- Membrane Proteins/metabolism
- Nephrosis, Lipoid/diagnosis
- Nephrosis, Lipoid/genetics
- Nephrosis, Lipoid/metabolism
- Nephrosis, Lipoid/pathology
- Predictive Value of Tests
- Receptors, Urokinase Plasminogen Activator/genetics
- Receptors, Urokinase Plasminogen Activator/metabolism
- WT1 Proteins/genetics
- WT1 Proteins/metabolism
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Affiliation(s)
- Lívia Helena de Morais Pereira
- Institute of Biological and Natural Sciences, Discipline of General Pathology, Federal University of Triangulo Mineiro, Uberaba, Minas Gerais, Brazil
| | - Crislaine Aparecida da Silva
- Institute of Biological and Natural Sciences, Discipline of General Pathology, Federal University of Triangulo Mineiro, Uberaba, Minas Gerais, Brazil
| | | | - Liliane Silvano Araújo
- Institute of Biological and Natural Sciences, Discipline of General Pathology, Federal University of Triangulo Mineiro, Uberaba, Minas Gerais, Brazil
| | - Laura Penna Rocha
- Institute of Biological and Natural Sciences, Discipline of General Pathology, Federal University of Triangulo Mineiro, Uberaba, Minas Gerais, Brazil
| | - Marcelo Bernardes da Rocha Reis
- Institute of Biological and Natural Sciences, Discipline of General Pathology, Federal University of Triangulo Mineiro, Uberaba, Minas Gerais, Brazil
| | - Fernando Silva Ramalho
- Department of Pathology and Forensic Medicine, Ribeirão Preto Faculty of Medicine of São Paulo University, Ribeirão Preto, São Paulo, Brazil
| | - Rosana Rosa Miranda Corrêa
- Institute of Biological and Natural Sciences, Discipline of General Pathology, Federal University of Triangulo Mineiro, Uberaba, Minas Gerais, Brazil
| | - Marcos Vinicius Silva
- Institute of Biological and Natural Sciences, Discipline of Parasitology, Federal University of Triangulo Mineiro, Uberaba, Minas Gerais, Brazil
| | - Marlene Antonia Reis
- Institute of Biological and Natural Sciences, Discipline of General Pathology, Federal University of Triangulo Mineiro, Uberaba, Minas Gerais, Brazil
| | - Juliana Reis Machado
- Institute of Biological and Natural Sciences, Discipline of General Pathology, Federal University of Triangulo Mineiro, Uberaba, Minas Gerais, Brazil
- * E-mail:
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10
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Yuvashree M, Gokulakannan R, Ganesh RN, Viswanathan P. Enhanced Therapeutic Potency of Nanoemulsified Garlic Oil Blend Towards Renal Abnormalities in Pre-diabetic Rats. Appl Biochem Biotechnol 2019; 188:338-356. [PMID: 30450513 DOI: 10.1007/s12010-018-2919-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Accepted: 11/05/2018] [Indexed: 02/05/2023]
Abstract
The therapeutic potency of ultrasonic nanoemulsified garlic oil blend using a non-ionic surfactant (Tween 80) was assessed on pre-diabetic Wistar rats with microalbuminuria. The pre-diabetic condition was induced in male albino Wistar rats by supplementing high-fat diet. The prolonged period of the pre-diabetic state caused renal dysfunctioning, which was indicated by microalbuminuria. Treatment of pre-diabetic rats with nanoemulsified garlic oil blend significantly ameliorated the lipid profile (p < 0.001), urinary albumin (p < 0.01), microprotein (p < 0.001), urinary triglycerides (p < 0.01), serum triglycerides (p < 0.01), serum albumin (p < 0.05), and protein levels (p < 0.01) in comparison to treatment of pre-diabetic rats with garlic oil blend or atorvastatin. Similarly, histopathological investigations indicated a remarkable attenuation in the mesangial expansion and proliferation, glomerular and tubular basement membrane thickening, and the tubular lipid deposits on administering nanoemulsified garlic oil blend than garlic oil blend or atorvastatin. Moreover, nanoemulsified garlic oil blend significantly promoted renal podocin gene expression by 3.98-fold (p < 0.001) and attenuated increased urinary podocin level by 2.92-fold (p < 0.01). Thus, our study affirms that the efficacy of garlic oil blend was augmented upon nanoemulsification, which substantially ameliorated the renal abnormalities observed in the pre-diabetic condition than garlic oil blend or atorvastatin.
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Affiliation(s)
- Muralidaran Yuvashree
- Renal Research Lab, Centre for Biomedical Research, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632 014, India
| | - Ragavan Gokulakannan
- Renal Research Lab, Centre for Biomedical Research, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632 014, India
| | - Rajesh Nachiappa Ganesh
- Department of Pathology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Dhanvantrinagar, Puducherry, India
| | - Pragasam Viswanathan
- Renal Research Lab, Centre for Biomedical Research, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632 014, India.
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11
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Nawata A, Hisano S, Shimajiri S, Wang KY, Tanaka Y, Nakayama T. Podocyte and endothelial cell injury lead to nephrotic syndrome in proliferative lupus nephritis. Histopathology 2018; 72:1084-1092. [PMID: 29247494 DOI: 10.1111/his.13454] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Accepted: 12/10/2017] [Indexed: 01/12/2023]
Abstract
AIMS Nephrotic syndrome (NS) is a major manifestation of lupus nephritis (LN). The dysregulation of podocytes, the glomerular basement membrane (GBM) and endothelial cells (ECs) results in proteinuria in glomerular diseases. The aim of our study was to clarify whether the dysregulation of these barriers is associated with NS in proliferative LN and membranous LN. METHODS AND RESULTS Fifty-six patients with NS, including minimal change NS in 15, primary membranous nephropathy (PMN) in 13, class III/IV LN in 15, and class V LN in 13, were enrolled in this study. Subjects with idiopathic haematuria were assigned as controls. Glomerular expression of Wilms tumour protein 1 (WT1), nephrin, synaptopodin and podocalyxin was evaluated by immunohistochemistry (IHC) and real-time quantitative reverse transcription polymerase chain reaction. EC injury was evaluated by CD31 immunostaining and electron microscopy (EM). Reduced expression of WT1, nephrin and synaptopodin was found in PMN, class III/IV LN and class V LN as compared with controls by IHC and mRNA analysis. Reduced expression of these molecules was not different between class III/IV LN and class V LN. Reduced numbers of CD31-positive ECs were found in class III/IV LN as compared with class V LN. EC injury showing subendothelial widening on EM was apparent in class III/IV LN as compared with class V LN. Foot process effacement was found only along the GBM showing EC injury in class III/IV LN. CONCLUSIONS Our study suggests that coexistence of podocyte and EC injury may lead to NS in proliferative LN. Podocyte damage alone leads to NS in membranous LN.
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Affiliation(s)
- Aya Nawata
- Department of Pathology, University of Occupational and Environmental Health, Kitakyushu, Japan.,The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Satoshi Hisano
- Department of Pathology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Shohei Shimajiri
- Department of Pathology, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Ke-Yong Wang
- Department of Pathology, University of Occupational and Environmental Health, Kitakyushu, Japan.,Shared-Use Research Centre, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Yoshiya Tanaka
- The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Toshiyuki Nakayama
- Department of Pathology, University of Occupational and Environmental Health, Kitakyushu, Japan
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12
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Siegerist F, Ribback S, Dombrowski F, Amann K, Zimmermann U, Endlich K, Endlich N. Structured illumination microscopy and automatized image processing as a rapid diagnostic tool for podocyte effacement. Sci Rep 2017; 7:11473. [PMID: 28904359 PMCID: PMC5597580 DOI: 10.1038/s41598-017-11553-x] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Accepted: 08/22/2017] [Indexed: 01/19/2023] Open
Abstract
The morphology of podocyte foot processes is obligatory for renal function. Here we describe a method for the superresolution-visualization of podocyte foot processes using structured illumination microscopy of the slit diaphragm, which before has only been achieved by electron microscopy. As a proof of principle, we measured a mean foot process width of 0.249 ± 0.068 µm in healthy kidneys and a significant higher mean foot process width of 0.675 ± 0.256 µm in minimal change disease patients indicating effacement of foot processes. We then hypothesized that the slit length per glomerular capillary surface area (slit diaphragm density) could be used as an equivalent for the diagnosis of effacement. Using custom-made software we measured a mean value of 3.10 ± 0.27 µm−1 in healthy subjects and 1.83 ± 0.49 µm−1 in the minimal change disease patients. As foot process width was highly correlated with slit diaphragm density (R2 = 0.91), we concluded that our approach is a valid method for the diagnosis of foot process effacement. In summary, we present a new technique to quantify podocyte damage, which combines superresolution microscopy with automatized image processing. Due to its diverse advantages, we propose this technique to be included into routine diagnostics of glomerular histopathology.
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Affiliation(s)
- Florian Siegerist
- Department of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany
| | - Silvia Ribback
- Department of Pathology, University Medicine Greifswald, Greifswald, Germany
| | - Frank Dombrowski
- Department of Pathology, University Medicine Greifswald, Greifswald, Germany
| | - Kerstin Amann
- Department of Nephropathology, Institute of Pathology, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Uwe Zimmermann
- Department of Urology, University Medicine Greifswald, Greifswald, Germany
| | - Karlhans Endlich
- Department of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany
| | - Nicole Endlich
- Department of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany.
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13
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Kim EY, Roshanravan H, Dryer SE. Changes in podocyte TRPC channels evoked by plasma and sera from patients with recurrent FSGS and by putative glomerular permeability factors. Biochim Biophys Acta Mol Basis Dis 2017; 1863:2342-2354. [PMID: 28629718 PMCID: PMC5557291 DOI: 10.1016/j.bbadis.2017.06.010] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Revised: 06/13/2017] [Accepted: 06/15/2017] [Indexed: 12/13/2022]
Abstract
Primary forms of focal and segmental glomerulosclerosis (FSGS) are driven by circulating factors that cause dysfunction or loss podocytes. Rare genetic forms of FSGS can be caused by mutations in TRPC6, which encodes a Ca2+-permeable cationic channel expressed in mesangial cells and podocytes; and NPHS2, which encodes podocin, a TRPC6-binding protein expressed in podocyte slit diaphragm domains. Here we observed that exposing immortalized mouse podocytes to serum or plasma from recurrent FSGS patients for 24h increased the steady-state cell-surface abundance of TRPC6, accompanied by an increase in currents through endogenous TRPC6 channels evoked by a hypoosmotic stretch stimulus. These effects were mimicked by the soluble urokinase receptor (suPAR) and by tumor necrosis factor (TNF), circulating factors implicated in nephrotic syndromes. Most but not all of the recurrent FSGS plasma samples that we examined also caused a loss of podocin over a period of several hours. The loss of podocin was also seen following exposure to suPAR but not TNF. However, TNF increased the effects of suPAR on TRPC6 and podocin, and TNF and suPAR are required for the full effects of one of the recurrent FSGS plasma samples. The actions of FSGS plasma, suPAR and TNF on surface abundance of TRPC6 were blocked by cilengitide, an inhibitor of αvβ3-integrin signaling. These data suggest that primary FSGS is a heterogeneous condition mediated by multiple circulating factors, and support TRPC6 and αvβ3-integrin as potential therapeutic targets.
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Affiliation(s)
- Eun Young Kim
- Department of Biology and Biochemistry, University of Houston, Houston, TX, USA
| | - Hila Roshanravan
- Department of Biology and Biochemistry, University of Houston, Houston, TX, USA
| | - Stuart E Dryer
- Department of Biology and Biochemistry, University of Houston, Houston, TX, USA; Department of Medicine, Division of Nephrology, Baylor College of Medicine, Houston, TX, USA.
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14
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Arruda-Junior DF, Martins FL, Dariolli R, Jensen L, Antonio EL, Dos Santos L, Tucci PJF, Girardi ACC. Dipeptidyl Peptidase IV Inhibition Exerts Renoprotective Effects in Rats with Established Heart Failure. Front Physiol 2016; 7:293. [PMID: 27462276 PMCID: PMC4941796 DOI: 10.3389/fphys.2016.00293] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2016] [Accepted: 06/27/2016] [Indexed: 12/14/2022] Open
Abstract
Circulating dipeptidyl peptidase IV (DPPIV) activity is associated with worse cardiovascular outcomes in humans and experimental heart failure (HF) models, suggesting that DPPIV may play a role in the pathophysiology of this syndrome. Renal dysfunction is one of the key features of HF, but it remains to be determined whether DPPIV inhibitors are capable of improving cardiorenal function after the onset of HF. Therefore, the present study aimed to test the hypothesis that DPPIV inhibition by vildagliptin improves renal water and salt handling and exerts anti-proteinuric effects in rats with established HF. To this end, male Wistar rats were subjected to left ventricle (LV) radiofrequency ablation or sham operation. Six weeks after surgery, radiofrequency-ablated rats who developed HF were randomly divided into two groups and treated for 4 weeks with vildagliptin (120 mg/kg/day) or vehicle by oral gavage. Echocardiography was performed before (pretreatment) and at the end of treatment (post-treatment) to evaluate cardiac function. The fractional area change (FAC) increased (34 ± 5 vs. 45 ± 3%, p < 0.05), and the isovolumic relaxation time decreased (33 ± 2 vs. 27 ± 1 ms; p < 0.05) in HF rats treated with vildagliptin (post-treatment vs. pretreatment). On the other hand, cardiac dysfunction deteriorated further in vehicle-treated HF rats. Renal function was impaired in vehicle-treated HF rats as evidenced by fluid retention, low glomerular filtration rate (GFR) and high levels of urinary protein excretion. Vildagliptin treatment restored urinary flow, GFR, urinary sodium and urinary protein excretion to sham levels. Restoration of renal function in HF rats by DPPIV inhibition was associated with increased active glucagon-like peptide-1 (GLP-1) serum concentration, reduced DPPIV activity and increased activity of protein kinase A in the renal cortex. Furthermore, the anti-proteinuric effect of vildagliptin treatment in rats with established HF was associated with upregulation of the apical proximal tubule endocytic receptor megalin and of the podocyte main slit diaphragm proteins nephrin and podocin. Collectively, these findings demonstrate that DPPIV inhibition exerts renoprotective effects and ameliorates cardiorenal function in rats with established HF. Long-term studies with DPPIV inhibitors are needed to ascertain whether these effects ultimately translate into improved clinical outcomes.
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Affiliation(s)
| | - Flavia L Martins
- Heart Institute (InCor), University of São Paulo Medical School São Paulo, Brazil
| | - Rafael Dariolli
- Heart Institute (InCor), University of São Paulo Medical School São Paulo, Brazil
| | - Leonardo Jensen
- Heart Institute (InCor), University of São Paulo Medical School São Paulo, Brazil
| | - Ednei L Antonio
- Cardiology Division, Department of Medicine, Federal University of São Paulo São Paulo, Brazil
| | - Leonardo Dos Santos
- Department of Physiological Sciences, Federal University of Espírito Santo Vitória, Brazil
| | - Paulo J F Tucci
- Cardiology Division, Department of Medicine, Federal University of São Paulo São Paulo, Brazil
| | - Adriana C C Girardi
- Heart Institute (InCor), University of São Paulo Medical School São Paulo, Brazil
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15
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Clinical and histopathological features resembling those of human focal segmental glomerulosclerosis in a cat with nonimmune-mediated glomerulonephropathy. BMC Vet Res 2015; 11:251. [PMID: 26445234 PMCID: PMC4596470 DOI: 10.1186/s12917-015-0569-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2015] [Accepted: 09/30/2015] [Indexed: 11/29/2022] Open
Abstract
Background Nonimmune-mediated glomerulonephropathies are rarely reported in domestic animals with the exception of amyloidosis. Here we describe the pathological features and clinical course of a feline with protein-losing nonimmune-mediated glomerulonephropathy characterized by segmental glomerulosclerosis and severe podocyte injury. Case presentation A castrated male Japanese domestic cat aged 3 years and 8 months had hypertension, persistent proteinuria, and azotemia. Microscopic examination of a renal biopsy revealed many glomeruli with adhesion to the Bowman’s capsule and segmental sclerosis. The most characteristic ultrastructural glomerular feature was severe podocyte foot process effacement. No electron-dense deposits were observed. Immunofluorescence revealed no immune deposits, but abnormal expression of nephrin and podocin was detected in the glomeruli. These findings resemble those of human focal segmental glomerulosclerosis. The cat temporarily responded to treatment with angiotensin-converting enzyme inhibitors and prednisolone administration but died of progressive renal failure 32 months after biopsy. Conclusions The cat was diagnosed with nonimmune mediated glomerulonephropathy because of the absence of immune deposits and severe podocyte injury. To our knowledge, this is the first report of nonimmune-mediated glomerulonephropathy in a cat resembling human focal segmental glomerulosclerosis.
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16
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Bernardi S, Toffoli B, Zennaro C, Bossi F, Losurdo P, Michelli A, Carretta R, Mulatero P, Fallo F, Veglio F, Fabris B. Aldosterone effects on glomerular structure and function. J Renin Angiotensin Aldosterone Syst 2015; 16:730-8. [PMID: 26283678 DOI: 10.1177/1470320315595568] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Accepted: 06/11/2015] [Indexed: 11/16/2022] Open
Abstract
OBJECTIVE Experimental evidence suggests that aldosterone directly contributes to organ damage by promoting cell growth, fibrosis, and inflammation. Based on these premises, this work aimed to assess the glomerular effects of aldosterone, alone and in combination with salt. METHODS After undergoing uninephrectomy, 75 rats were allocated to five groups: control, salt diet, aldosterone, aldosterone + salt diet, aldosterone + salt diet and eplerenone, and they were all studied for four weeks. We focused on glomerular structural, functional, and molecular changes, including slit diaphragm components, local renin-angiotensin system activation, as well as pro-oxidative and profibrotic changes. RESULTS Aldosterone significantly increased systolic blood pressure, led to glomerular hypertrophy, mesangial expansion, and it significantly increased the glomerular permeability to albumin and the albumin excretion rate, indicating the presence of glomerular damage. These effects were worsened by adding salt to aldosterone, while they were reduced by eplerenone. Aldosterone-induced glomerular damage was associated with glomerular angiotensin-converting enzyme (ACE) 2 downregulation, with ACE/ACE2 ratio increase, ANP decrease, as well as with glomerular pro-oxidative and profibrotic changes. CONCLUSIONS Aldosterone damages not only the structure but also the function of the glomerulus. ACE/ACE2 upregulation, ACE2 and ANP downregulation, and pro-oxidative and profibrotic changes are possible mechanisms accounting for aldosterone-induced glomerular injury.
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Affiliation(s)
- Stella Bernardi
- Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Teaching Hospital, Italy
| | - Barbara Toffoli
- Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Teaching Hospital, Italy Centre for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, Switzerland
| | - Cristina Zennaro
- Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Teaching Hospital, Italy
| | - Fleur Bossi
- Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Teaching Hospital, Italy
| | - Pasquale Losurdo
- Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Teaching Hospital, Italy
| | - Andrea Michelli
- Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Teaching Hospital, Italy
| | - Renzo Carretta
- Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Teaching Hospital, Italy
| | - Paolo Mulatero
- Division of Internal Medicine and Hypertension, University of Torino, Italy
| | - Francesco Fallo
- Department of Medical and Surgical Sciences, University of Padova, Italy
| | - Franco Veglio
- Division of Internal Medicine and Hypertension, University of Torino, Italy
| | - Bruno Fabris
- Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Teaching Hospital, Italy
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17
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Podocyte proteins in congenital and minimal change nephrotic syndrome. Clin Exp Nephrol 2014; 19:481-8. [PMID: 25117488 DOI: 10.1007/s10157-014-1020-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2014] [Accepted: 07/31/2014] [Indexed: 12/17/2022]
Abstract
BACKGROUND Podocyte foot process effacement is a uniform finding in kidneys with heavy proteinuria. Its molecular mechanisms, however, are unsolved. We analyzed the expression of podocyte proteins in two kidney disorders: Congenital nephrotic syndrome of the Finnish type (CNF) and minimal change nephrotic syndrome (MCNS). METHODS Immunoperoxidase and immunofluorescence stainings were used to semiquantitatively analyze the expression of 13 and 4 podocyte proteins from different cellular compartments in CNF and MCNS, respectively. RESULTS The expression of a major slit diaphragm (SD) protein, Neph 1, showed a 46-fold decrease (p < 0.0001) in CNF kidneys as compared to controls. The three cytosolic adaptor proteins, podocin, NCK1/2, CD2AP, connecting SD proteins to the actin cytoskeleton were slightly upregulated (1.1-fold, 1.4-fold, and 3.3-fold, respectively). Also, the staining of the two actin-regulator proteins, ACTN4 and INF2, was modestly increased (2.2-fold and 1.7-fold, respectively, p < 0.0001). Staining for α3-integrin showed 1.9-fold increase (p < 0.0001) indicating that the major podocyte anchoring complex, α3β1, was well preserved in CNF glomeruli. In contrast to CNF kidneys, Neph1 FAT1, ACTN4, and CD2AP were quite normally expressed in proteinuric and non-proteinuric MCNS kidneys. CONCLUSION CNF kidneys lacking nephrin show decreased expression of other SD proteins but not cytosolic podocyte proteins involved in the foot process architecture or function. In MCNS kidneys, these changes in expression were not observed.
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18
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Resveratrol increases nephrin and podocin expression and alleviates renal damage in rats fed a high-fat diet. Nutrients 2014; 6:2619-31. [PMID: 25025298 PMCID: PMC4113760 DOI: 10.3390/nu6072619] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2014] [Revised: 06/09/2014] [Accepted: 06/27/2014] [Indexed: 11/17/2022] Open
Abstract
Resveratrol is well known for its anti-inflammation and anti-oxidant properties, and has been shown to be effective in alleviating the development of obesity. The purpose of this investigation was to analyze the effect of resveratrol on renal damage in obese rats induced by a high-fat diet (HFD) and its possible mechanisms. Male Sprague-Dawley rats were divided into three groups: control, HFD, and HFD plus resveratrol (treated with 100 mg/kg/day resveratrol). Body weight, serum and urine metabolic parameters, and kidney histology were measured. Meanwhile, the activities of nuclear factor-κB (NF-κB) and superoxide dismutase (SOD), the content of malondialdehyde (MDA), and the protein levels of tumor necrosis factor (TNF-α), monocyte chemotactic protein-1 (MCP-1), nephrin and podocin in kidney were detected. Our work showed that resveratrol alleviated dyslipidemia and renal damage induced by HFD, decreased MDA level and increased SOD activity. Furthermore, the elevated NF-κB activity, increased TNF-α and MCP-1 levels, and reduced expressions of nephrin and podocin induced by HFD were significantly reversed by resveratrol. These results suggest resveratrol could ameliorate renal injury in rats fed a HFD, and the mechanisms are associated with suppressing oxidative stress and NF-κB signaling pathway that in turn up-regulate nephrin and podocin protein expression.
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19
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Ding ZH, Xu LM, Wang SZ, Kou JQ, Xu YL, Chen CX, Yu HP, Qin ZH, Xie Y. Ameliorating Adriamycin-Induced Chronic Kidney Disease in Rats by Orally Administrated Cardiotoxin from Naja naja atra Venom. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2014; 2014:621756. [PMID: 24876873 PMCID: PMC4021839 DOI: 10.1155/2014/621756] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/13/2014] [Revised: 04/11/2014] [Accepted: 04/12/2014] [Indexed: 01/27/2023]
Abstract
Previous studies reported the oral administration of Naja naja atra venom (NNAV) reduced adriamycin-induced chronic kidney damage. This study investigated the effects of intragastric administrated cardiotoxin from Naja naja atra venom on chronic kidney disease in rats. Wistar rats were injected with adriamycin (ADR; 6 mg/kg body weight) via the tail vein to induce chronic kidney disease. The cardiotoxin was administrated daily by intragastric injection at doses of 45, 90, and 180 μ g/kg body weight until the end of the protocol. The rats were placed in metabolic cages for 24 hours to collect urine, for determination of proteinuria, once a week. After 6 weeks, the rats were sacrificed to determine serum profiles relevant to chronic kidney disease, including albumin, total cholesterol, phosphorus, blood urea nitrogen, and serum creatinine. Kidney histology was examined with hematoxylin and eosin, periodic acid-Schiff, and Masson's trichrome staining. The levels of kidney podocin were analyzed by Western blot analysis and immunofluorescence. We found that cardiotoxin reduced proteinuria and can improve biological parameters in the adriamycin-induced kidney disease model. Cardiotoxin also reduced adriamycin-induced kidney pathology, suggesting that cardiotoxin is an active component of NNAV for ameliorating adriamycin-induced kidney damage and may have a potential therapeutic value on chronic kidney disease.
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Affiliation(s)
- Zhi-Hui Ding
- The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China
| | - Li-Min Xu
- The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China
| | - Shu-Zhi Wang
- Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Soochow University School of Medicine, Suzhou 215123, Jiangsu, China
| | - Jian-Qun Kou
- Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Soochow University School of Medicine, Suzhou 215123, Jiangsu, China
| | - Yin-Li Xu
- Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Soochow University School of Medicine, Suzhou 215123, Jiangsu, China
| | - Cao-Xin Chen
- Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Soochow University School of Medicine, Suzhou 215123, Jiangsu, China
| | - Hong-Pei Yu
- The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China
| | - Zheng-Hong Qin
- Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Soochow University School of Medicine, Suzhou 215123, Jiangsu, China
| | - Yan Xie
- The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China
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