NADPH oxidase Nox5 accelerates renal injury in diabetic nephropathy

Jay C. Jha, Claudine Banal, Jun Okabe, Stephen P. Gray, Thushan Hettige, Bryna S.M. Chow, Vicki Thallas-Bonke, Lisanne De Vos, Chet E. Holterman, Melinda T. Coughlan, David A. Power, Alison Skene, Elif I. Ekinci, Mark E. Cooper, Rhian M. Touyz, Chris R. Kennedy, Karin Jandeleit-Dahm

Research output: Contribution to journalArticleResearchpeer-review

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-b1–induced enhanced ROS production, increased expression of profibrotic and proinflammatory mediators, and increased TRPC6, PKC-a, 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.

Original languageEnglish
Pages (from-to)2691-2703
Number of pages13
JournalDiabetes
Volume66
Issue number10
DOIs
Publication statusPublished - 1 Oct 2017

Cite this

Jha, Jay C. ; Banal, Claudine ; Okabe, Jun ; Gray, Stephen P. ; Hettige, Thushan ; Chow, Bryna S.M. ; Thallas-Bonke, Vicki ; Vos, Lisanne De ; 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. / NADPH oxidase Nox5 accelerates renal injury in diabetic nephropathy. In: Diabetes. 2017 ; Vol. 66, No. 10. pp. 2691-2703.
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title = "NADPH oxidase Nox5 accelerates renal injury in diabetic nephropathy",
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-b1–induced enhanced ROS production, increased expression of profibrotic and proinflammatory mediators, and increased TRPC6, PKC-a, 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.",
author = "Jha, {Jay C.} and Claudine Banal and Jun Okabe and Gray, {Stephen P.} and Thushan Hettige and Chow, {Bryna S.M.} and Vicki Thallas-Bonke and Vos, {Lisanne De} and Holterman, {Chet E.} and Coughlan, {Melinda T.} and Power, {David A.} and Alison Skene and Ekinci, {Elif I.} and Cooper, {Mark E.} and Touyz, {Rhian M.} and Kennedy, {Chris R.} and Karin Jandeleit-Dahm",
year = "2017",
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Jha, JC, Banal, C, Okabe, J, Gray, SP, Hettige, T, Chow, BSM, Thallas-Bonke, V, Vos, LD, Holterman, CE, Coughlan, MT, Power, DA, Skene, A, Ekinci, EI, Cooper, ME, Touyz, RM, Kennedy, CR & Jandeleit-Dahm, K 2017, 'NADPH oxidase Nox5 accelerates renal injury in diabetic nephropathy' Diabetes, vol. 66, no. 10, pp. 2691-2703. https://doi.org/10.2337/db16-1585

NADPH oxidase Nox5 accelerates renal injury in diabetic nephropathy. / Jha, Jay C.; Banal, Claudine; Okabe, Jun; Gray, Stephen P.; Hettige, Thushan; Chow, Bryna S.M.; Thallas-Bonke, Vicki; Vos, Lisanne De; 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.

In: Diabetes, Vol. 66, No. 10, 01.10.2017, p. 2691-2703.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Banal, Claudine

AU - Okabe, Jun

AU - Gray, Stephen P.

AU - Hettige, Thushan

AU - Chow, Bryna S.M.

AU - Thallas-Bonke, Vicki

AU - Vos, Lisanne De

AU - Holterman, Chet E.

AU - Coughlan, Melinda T.

AU - Power, David A.

AU - Skene, Alison

AU - Ekinci, Elif I.

AU - Cooper, Mark E.

AU - Touyz, Rhian M.

AU - Kennedy, Chris R.

AU - Jandeleit-Dahm, Karin

PY - 2017/10/1

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N2 - 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-b1–induced enhanced ROS production, increased expression of profibrotic and proinflammatory mediators, and increased TRPC6, PKC-a, 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.

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