NADPH oxidase-Nox5 accelerates renal injury in a mouse model of diabetic nephropathy

Jha, J.C. et al. (2017) NADPH oxidase-Nox5 accelerates renal injury in a mouse model of diabetic nephropathy. Journal of the American Society of Nephrology, 66(10), pp. 2691-2703. (doi: 10.2337/db16-1585) (PMID:28747378)

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Abstract

NADPH oxidase–derived excessive production of reactive oxygen species (ROS) in the kidney plays a key role in mediating renal injury in diabetes. Pathological changes in diabetes include mesangial expansion and accumulation of extracellular matrix (ECM) leading to glomerulosclerosis. There is a paucity of data about the role of the Nox5 isoform of NADPH oxidase in animal models of diabetic nephropathy since Nox5 is absent in the mouse genome. Thus, we examined the role of Nox5 in human diabetic nephropathy in human mesangial cells and in an inducible human Nox5 transgenic mouse exposed to streptozotocin-induced diabetes. In human kidney biopsies, Nox5 was identified to be expressed in glomeruli, which appeared to be increased in diabetes. Colocalization demonstrated Nox5 expression in mesangial cells. In vitro, silencing of Nox5 in human mesangial cells was associated with attenuation of the hyperglycemia and TGF-β1–induced enhanced ROS production, increased expression of profibrotic and proinflammatory mediators, and increased TRPC6, PKC-α, and PKC-β expression. In vivo, vascular smooth muscle cell/mesangial cell–specific overexpression of Nox5 in a mouse model of diabetic nephropathy showed enhanced glomerular ROS production, accelerated glomerulosclerosis, mesangial expansion, and ECM protein (collagen IV and fibronectin) accumulation as well as increased macrophage infiltration and expression of the proinflammatory chemokine MCP-1. Collectively, this study provides evidence of a role for Nox5 and its derived ROS in promoting progression of diabetic nephropathy.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Touyz, Professor Rhian
Authors: Jha, J.C., Banal, C., Okabe, J., Gray, S.P., Hettige, T., Chow, B.S.M., Thallas-Bonke, V., Holterman, C.E., Cooper, M.E., Touyz, R.M., Kennedy, C.R., and Jandeleit-Dahm, K.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Journal of the American Society of Nephrology
Publisher:American Society of Nephrology
ISSN:1046-6673
ISSN (Online):1533-3450

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
690421Glasgow Molecular Pathology (GMP) NodeKarin OienMedical Research Council (MRC)MR/N005813/1ICS - EXPERIMENTAL THERAPEUTICS