PMID- 26508318 OWN - NLM STAT- MEDLINE DCOM- 20161019 LR - 20190407 IS - 1432-0428 (Electronic) IS - 0012-186X (Print) IS - 0012-186X (Linking) VI - 59 IP - 2 DP - 2016 Feb TI - Podocyte-specific Nox4 deletion affords renoprotection in a mouse model of diabetic nephropathy. PG - 379-89 LID - 10.1007/s00125-015-3796-0 [doi] AB - AIMS/HYPOTHESIS: Changes in podocyte morphology and function are associated with albuminuria and progression of diabetic nephropathy. NADPH oxidase 4 (NOX4) is the main source of reactive oxygen species (ROS) in the kidney and Nox4 is upregulated in podocytes in response to high glucose. We assessed the role of NOX4-derived ROS in podocytes in vivo in a model of diabetic nephropathy using a podocyte-specific NOX4-deficient mouse, with a major focus on the development of albuminuria and ultra-glomerular structural damage. METHODS: Streptozotocin-induced diabetes-associated changes in renal structure and function were studied in male floxedNox4 and podocyte-specific, NOX4 knockout (podNox4KO) mice. We assessed albuminuria, glomerular extracellular matrix accumulation and glomerulosclerosis, and markers of ROS and inflammation, as well as glomerular basement membrane thickness, effacement of podocytes and expression of the podocyte-specific protein nephrin. RESULTS: Podocyte-specific Nox4 deletion in streptozotocin-induced diabetic mice attenuated albuminuria in association with reduced vascular endothelial growth factor (VEGF) expression and prevention of the diabetes-induced reduction in nephrin expression. In addition, podocyte-specific Nox4 deletion reduced glomerular accumulation of collagen IV and fibronectin, glomerulosclerosis and mesangial expansion, as well as glomerular basement membrane thickness. Furthermore, diabetes-induced increases in renal ROS, glomerular monocyte chemoattractant protein-1 (MCP-1) and protein kinase C alpha (PKC-alpha) were attenuated in podocyte-specific NOX4-deficient mice. CONCLUSIONS/INTERPRETATION: Collectively, this study shows the deleterious effect of Nox4 expression in podocytes by promoting podocytopathy in association with albuminuria and extracellular matrix accumulation in experimental diabetes, emphasising the role of NOX4 as a target for new renoprotective agents. FAU - Jha, Jay C AU - Jha JC AD - Diabetes Complications Division, Baker IDI Heart & Diabetes Research Institute, PO Box 6492, St Kilda Rd, Melbourne, VIC, 8008, Australia. AD - Department of Medicine, Monash University, Melbourne, VIC, Australia. FAU - Thallas-Bonke, Vicki AU - Thallas-Bonke V AD - Diabetes Complications Division, Baker IDI Heart & Diabetes Research Institute, PO Box 6492, St Kilda Rd, Melbourne, VIC, 8008, Australia. FAU - Banal, Claudine AU - Banal C AD - Diabetes Complications Division, Baker IDI Heart & Diabetes Research Institute, PO Box 6492, St Kilda Rd, Melbourne, VIC, 8008, Australia. FAU - Gray, Stephen P AU - Gray SP AD - Diabetes Complications Division, Baker IDI Heart & Diabetes Research Institute, PO Box 6492, St Kilda Rd, Melbourne, VIC, 8008, Australia. FAU - Chow, Bryna S M AU - Chow BS AD - Diabetes Complications Division, Baker IDI Heart & Diabetes Research Institute, PO Box 6492, St Kilda Rd, Melbourne, VIC, 8008, Australia. FAU - Ramm, Georg AU - Ramm G AD - Monash Micro-imaging, Monash University, Melbourne, VIC, Australia. FAU - Quaggin, Susan E AU - Quaggin SE AD - Robert H. Lurie Medical Research Center, Chicago, IL, USA. FAU - Cooper, Mark E AU - Cooper ME AD - Diabetes Complications Division, Baker IDI Heart & Diabetes Research Institute, PO Box 6492, St Kilda Rd, Melbourne, VIC, 8008, Australia. AD - Department of Medicine, Monash University, Melbourne, VIC, Australia. FAU - Schmidt, Harald H H W AU - Schmidt HH AD - Department of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), Faculty of Medicine, Health & Life Science, Maastricht University, Maastricht, the Netherlands. FAU - Jandeleit-Dahm, Karin A AU - Jandeleit-Dahm KA AD - Diabetes Complications Division, Baker IDI Heart & Diabetes Research Institute, PO Box 6492, St Kilda Rd, Melbourne, VIC, 8008, Australia. karin.jandeleit-dahm@bakeridi.edu.au. AD - Department of Medicine, Monash University, Melbourne, VIC, Australia. karin.jandeleit-dahm@bakeridi.edu.au. LA - eng GR - R01 HL124120/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20151028 PL - Germany TA - Diabetologia JT - Diabetologia JID - 0006777 RN - 5W494URQ81 (Streptozocin) RN - EC 1.6.3.- (NADPH Oxidase 4) RN - EC 1.6.3.- (NADPH Oxidases) RN - EC 1.6.3.- (Nox4 protein, mouse) SB - IM MH - Albuminuria/genetics/pathology MH - Animals MH - Cytoprotection/*genetics MH - Diabetes Mellitus, Experimental/chemically induced/*complications/genetics MH - Diabetic Nephropathies/*genetics/pathology MH - Gene Deletion MH - Kidney/metabolism/pathology MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - NADPH Oxidase 4 MH - NADPH Oxidases/*genetics/metabolism MH - Organ Specificity/genetics MH - Podocytes/*metabolism/pathology MH - Streptozocin PMC - PMC6450410 MID - NIHMS868512 OTO - NOTNLM OT - Albuminuria OT - Diabetic nephropathy OT - Glomerular basement membrane OT - NADPH oxidase 4 OT - Podocyte OT - Reactive oxygen species COIS- Duality of interest statement: The authors declare that there is no duality of interest associated with this manuscript. EDAT- 2015/10/29 06:00 MHDA- 2016/11/12 06:00 PMCR- 2019/04/05 CRDT- 2015/10/29 06:00 PHST- 2015/07/06 00:00 [received] PHST- 2015/10/01 00:00 [accepted] PHST- 2015/10/29 06:00 [entrez] PHST- 2015/10/29 06:00 [pubmed] PHST- 2016/11/12 06:00 [medline] PHST- 2019/04/05 00:00 [pmc-release] AID - 10.1007/s00125-015-3796-0 [pii] AID - 10.1007/s00125-015-3796-0 [doi] PST - ppublish SO - Diabetologia. 2016 Feb;59(2):379-89. doi: 10.1007/s00125-015-3796-0. Epub 2015 Oct 28.