NADPH oxidase-nox5 accelerates renal injury in diabetic nephropathy

2017-07-26

Jha, Jay C

Banal, Claudine

Okabe, Jun

Gray, Stephen P

Hettige, Thushan

Chow, Bryna SM

Thallas-Bonke, Vicki

De Vos, Lisanne

Holterman, Chet E

Coughlan, Melinda T

Power, David A

Skene, Alison

Ekinci, Elif I

Cooper, Mark E

Touyz, Rhian M

Kennedy, Chris R

Jandeleit-Dahm, Karin

Journal Article

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10.2337/db16-1585

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 STZ-induced diabetes.In human kidney biopsies, Nox5 was identified to be expressed in glomeruli which appeared to be increased in diabetes. Co-localisation 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 pro-fibrotic and pro-inflammatory mediators as well as increased TRPC6, PKC- α and PKC- β expression. In vivo, vascular smooth muscle cell (VSMC)/mesangial cell specific over expression 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 pro-inflammatory chemokine MCP-1. Collectively, this study provides evidence of a role for Nox5 and its derived ROS in promoting progression of diabetic nephropathy.

link

Diabetes 2017; online first: 26 July

Diabetes