Catalase Overexpression Prevents Nuclear Factor Erythroid 2-Related Factor 2 Stimulation of Renal Angiotensinogen Gene Expression, Hypertension, and Kidney Injury in Diabetic Mice

被引：53

作者：

Abdo, Shaaban ^{[1
]}

Shi, Yixuan ^{[1
]}

Otoukesh, Abouzar ^{[1
]}

Ghosh, Anindya ^{[1
]}

Lo, Chao-Sheng ^{[1
]}

Chenier, Isabelle ^{[1
]}

Filep, Janos G. ^{[2
]}

Ingelfinger, Julie R. ^{[3
]}

Zhang, Shao Ling ^{[1
]}

Chan, John S. D. ^{[1
]}

机构：

[1] Univ Montreal, Res Ctr, Ctr Hosp Univ Montreal, Montreal, PQ, Canada

[2] Univ Montreal, Res Ctr, Hop Maisonneuve Rosemont, Montreal, PQ, Canada

[3] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pediat Nephrol Unit, Boston, MA USA

来源：

DIABETES | 2014年 / 63卷 / 10期

基金：

加拿大健康研究院; 美国国家卫生研究院;

关键词：

PROXIMAL TUBULAR CELLS; CONVERTING ENZYME-2 EXPRESSION; TRANSGENIC MICE; BARDOXOLONE METHYL; TUBULOINTERSTITIAL FIBROSIS; URINARY ANGIOTENSINOGEN; TRANSCRIPTION FACTOR; BLOOD-PRESSURE; CANCER CELLS; APOPTOSIS;

D O I：

10.2337/db13-1830

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

This study investigated the impact of catalase (Cat) overexpression in renal proximal tubule cells (RPTCs) on nuclear factor erythroid 2-related factor 2 (Nrf2) stimulation of angiotensinogen (Agt) gene expression and the development of hypertension and renal injury in diabetic Akita transgenic mice. Additionally, adult male mice were treated with the Nrf2 activator oltipraz with or without the inhibitor trigonelline. Rat RPTCs, stably transfected with plasmid containing either rat Agt or Nrf2 gene promoter, were also studied. Cat overexpression normalized systolic BP, attenuated renal injury, and inhibited RPTC Nrf2, Agt, and heme oxygenase-1 (HO-1) gene expression in Akita Cat transgenic mice compared with Akita mice. In vitro, high glucose level, hydrogen peroxide, and oltipraz stimulated Nrf2 and Agt gene expression; these changes were blocked by trigonelline, small interfering RNAs of Nrf2, antioxidants, or pharmacological inhibitors of nuclear factor-kappa B and p38 mitogen-activated protein kinase. The deletion of Nrf2-responsive elements in the rat Agt gene promoter abolished the stimulatory effect of oltipraz. Oltipraz administration also augmented Agt, HO-1, and Nrf2 gene expression in mouse RPTCs and was reversed by trigonelline. These data identify a novel mechanism, Nrf2-mediated stimulation of intrarenal Agt gene expression and activation of the renin-angiotensin system, by which hyperglycemia induces hypertension and renal injury in diabetic mice.

引用

页码：3483 / 3496

页数：14

共 48 条

[1]

Heterogeneous nuclear ribonucleoproteins F and K mediate insulin inhibition of renal angiotensinogen gene expression and prevention of hypertension and kidney injury in diabetic mice [J].