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 development of hypertension and renal injury in diabetic Akita transgenic (Tg) mice. Additionally, adult male mice were treated with the Nrf2 activator oltipraz ± an 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-Tg compared to Akita mice. In vitro, high glucose, hydrogen peroxide and oltipraz stimulated Nrf2 and Agt gene expression; these changes were blocked by trigonelline, small interfering RNA of Nrf2, antioxidants, or pharmacological inhibitors of NF-kB and p38 mitogen-activated protein kinase. 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.
- Received December 2, 2013.
- Accepted April 24, 2014.
- © 2014 by the American Diabetes Association.
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