Abstract: TH-PO693

Nuclear Factor Erythroid 2-Related Factor 2 Deficiency Attenuates Hypertension and Nephropathy via Up-Regulation of Renal Angiotensin Converting Enzyme-2 and Mas Receptor Expression in Diabetic Mice

Session Information

Category: Diabetes

  • 501 Diabetes Mellitus and Obesity: Basic - Experimental

Authors

  • Zhao, Shuiling, CRCHUM, MONTREAL, Quebec, Canada
  • Ghosh, Anindya, CRCHUM, University of Montreal, Montreal, Quebec, Canada
  • Lo, Chao-Sheng, CRCHUM, Universite de Montreal, Montreal, Quebec, Canada
  • Chenier, Isabelle, CHUM-Hotel Dieu Hosp, Montreal, Quebec, Canada
  • Filep, Janos G., Maisonneuve-Rosemont Hosp., Montreal, Quebec, Canada
  • Ingelfinger, Julie R., The New England Journal of Medicine, Boston, Massachusetts, United States
  • Zhang, Shao-Ling, Research Center of Centre Hospitalier de l Universite de Montreal (CRCHUM), Montreal, Quebec, Canada
  • Chan, John S.D., CRCHUM,University of Montreal, Montreal, Quebec, Canada
Background

We investigated the impact of nuclear factor erythroid 2-related factor 2 (Nrf2) deficiency on hypertension, kidney injury and renin-angiotensin system (RAS) gene expression in renal proximal tubule cells (RPTCs) in diabetic Akita (type 1 diabetes model) Nrf2 knockout (KO) mice and Akita mice treated with trigonelline (a Nrf2 inhibitor).

Methods

Male wild type (WT), Akita and Akita Nrf2 KO mice at 12 to 20 weeks were studied. Akita mice receiving trigonelline from weeks 12-18 +/- oltipraz (a Nrf2 activator) from weeks 16-18 were also studied. Blood glucose and systolic blood pressure were monitored weekly. Urinary albumin/creatinine ratio (ACR), angiotensin II (Ang II) and angiotensin 1-7 (Ang 1-7) levels were measured by ELISA. Kidneys were processed for histology. RAS mRNA and protein expression in renal proximal tubules (RPTs) were evaluated by RT-qPCR and Western blotting, respectively. We also performed Nrf2 knockdown in rat immortalized RPTCs (IRPTCs) stably transfected with plasmid containing rat angiotensinogen (Agt), angiotensin converting enzyme (ACE), angiotensin converting enzyme-2 (Ace2) or angiotensin 1-7 receptor (MasR) gene promoter.

Results

Nrf2 deficiency attenuated hypertension, renal hypertrophy, tubulointerstitial fibrosis, urinary ACR and Ang II, down-regulated RPTC Agt, ACE and pro-fibrotic gene expression and up-regulated Ace2 and MasR expression and urinary Ang 1-7 levels in Akita Nrf2 KO mice, compared to Akita mice. Similar changes were observed in Akita mice treated with trigonelline +/- oltipraz. Transfection of siRNA of Nrf2 prevented high glucose (HG, 25 mM)-stimulation of Agt and ACE expression and enhanced Ace2 and MasR expression in IRPTCs in vitro. Trigonelline decreased Agt/ACE and up-regulated Ace2/MasR mRNA expression in HG and these actions were reversed by oltipraz.

Conclusion

Nrf2 deficiency attenuates hypertension and kidney injury, via decreasing renal Agt/ACE expression and increasing Ace2/MasR expression. These results identify Nrf2 as a novel target for the prevention of hypertension and kidney injury in diabetes.

Funding

  • Government Support - Non-U.S.