Abstract: TH-PO411

AT2R Deficiency Accelerates Renal Dysfunction in Diabetic Progeny in a Sex-Dependent Manner

Session Information

Category: Nutrition, Inflammation, and Metabolism

  • 1401 Nutrition, Inflammation, Metabolism

Authors

  • Liao, Min-Chun, CRCHUM, University of Montreal, Montreal, Quebec, Canada
  • Chang, Shiao-Ying, CRCHUM, University of Montreal, Montreal, Quebec, Canada
  • Zhao, Xin-Ping, CRCHUM, University of Montreal, Montreal, Quebec, Canada
  • Lo, Chao-Sheng, CRCHUM, University of Montreal, Montreal, Quebec, Canada
  • Chenier, Isabelle, CRCHUM, University of Montreal, Montreal, Quebec, Canada
  • Ingelfinger, Julie R., The New England Journal of Medicine, Boston, Massachusetts, United States
  • Zhang, Shao-Ling, CRCHUM, University of Montreal, Montreal, Quebec, Canada
Background

Angiotensin type 2 receptor (AT2R) deficient mice (AT2RKO) exhibit a spectrum of congenital abnormalities of the kidney and urinary tract. We aimed to study whether AT2R deficiency in dams that also had diabetes mellitus would result in offspring with even more abnormalities in the urinary tract.

Methods

The offspring (male/female) of non-diabetic and diabetic dams of wild-type (WT) and AT2RKO mice were followed until 20 weeks of age. Systolic blood pressure, insulin sensitivity test (IST), albumin/creatinine ratio (ACR), glomerular filtration rate (GFR), renal morphology and gene expression including angiotensin converting enzyme (ACE), angiotensin converting enzyme 2 (ACE2), synaptopodin (Synpo) and tyrosine phosphatase SHP-1 (qPCR and immunohistochemistry) were assessed.

Results

Compared to the age- and sex-matched offspring of non-diabetic dams, diabetic progeny of both WT and AT2RKO mice developed more evidence of nephropathy (higher GFR and apparent glomerulosclerosis with podocyte loss) at 20 weeks of age, which were further aggravated in the offspring of AT2RKO diabetic dams, particularly female mice. Female offspring from diabetic AT2RKO dams developed insulin resistance, while male diabetic progeny of AT2RKO dams had normal IST. Renal ACE2, Synpo and SHP-1 gene expression were downregulated in both sex’s progenies of diabetic WT dams as well as male offspring of diabetic AT2RKO dams. In contrast, female offspring of AT2RKO dams had significant lower basal expression of ACE2, Synpo and SHP-1 genes in their kidneys, and those genes were completely blunted in female progeny of diabetic AT2RKO dams.

Conclusion

AT2R deficiency accelerated features of nephropathy in female progeny of diabetic dams, which might be due to loss of the protective effects of ACE2 and SHP1 expression in the kidney.

Funding

  • Government Support - Non-U.S.