Podocyte-specific Nox4 deletion affords renoprotection in a mouse model of diabetic nephropathy.
OBJECTIVE
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-α) were attenuated in podocyte-specific NOX4-deficient mice.


CONCLUSIONS
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.
Diabetes Complications Division, Baker IDI Heart & Diabetes Research Institute, PO Box 6492, St Kilda Rd, Melbourne, VIC, 8008, Australia.|Department of Medicine, Monash University, Melbourne, VIC, Australia.
Jay C
JC
Jha
Diabetes Complications Division, Baker IDI Heart & Diabetes Research Institute, PO Box 6492, St Kilda Rd, Melbourne, VIC, 8008, Australia.
Vicki
V
Thallas-Bonke
Diabetes Complications Division, Baker IDI Heart & Diabetes Research Institute, PO Box 6492, St Kilda Rd, Melbourne, VIC, 8008, Australia.
Claudine
C
Banal
Diabetes Complications Division, Baker IDI Heart & Diabetes Research Institute, PO Box 6492, St Kilda Rd, Melbourne, VIC, 8008, Australia.
Stephen P
SP
Gray
Diabetes Complications Division, Baker IDI Heart & Diabetes Research Institute, PO Box 6492, St Kilda Rd, Melbourne, VIC, 8008, Australia.
Bryna S M
BS
Chow
Monash Micro-imaging, Monash University, Melbourne, VIC, Australia.
Georg
G
Ramm
Robert H. Lurie Medical Research Center, Chicago, IL, USA.
Susan E
SE
Quaggin
Diabetes Complications Division, Baker IDI Heart & Diabetes Research Institute, PO Box 6492, St Kilda Rd, Melbourne, VIC, 8008, Australia.|Department of Medicine, Monash University, Melbourne, VIC, Australia.
Mark E
ME
Cooper
Department of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), Faculty of Medicine, Health & Life Science, Maastricht University, Maastricht, the Netherlands.
Harald H H W
HH
Schmidt
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.|Department of Medicine, Monash University, Melbourne, VIC, Australia. karin.jandeleit-dahm@bakeridi.edu.au.
Karin A
KA
Jandeleit-Dahm
D000419:Albuminuria / Q000235:genetics / Q000473:pathology; D000818:Animals; D019610:Cytoprotection / Q000235:genetics*; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications* / Q000235:genetics; D003928:Diabetic Nephropathies / Q000235:genetics* / Q000473:pathology; D017353:Gene Deletion; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics* / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D013311:Streptozocin
D013311:Streptozocin; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse
Albuminuria; Diabetic nephropathy; Glomerular basement membrane; NADPH oxidase 4; Podocyte; Reactive oxygen species