Kidney Week

Abstract: TH-PO411

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

Session Information

• Nutrition, Inflammation, Metabolism: Basic Mechanisms
  November 02, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Nutrition, Inflammation, and Metabolism

• 1401 Nutrition, Inflammation, Metabolism

Authors

• Liao, Min-Chun, CRCHUM, University of Montreal, Montreal, Quebec, Canada

Min-Chun Liao,

• Chang, Shiao-Ying, CRCHUM, University of Montreal, Montreal, Quebec, Canada

Shiao-Ying Chang,

• Zhao, Xin-Ping, CRCHUM, University of Montreal, Montreal, Quebec, Canada

Xin-Ping Zhao,

• Lo, Chao-Sheng, CRCHUM, University of Montreal, Montreal, Quebec, Canada

Chao-Sheng Lo,

• Chenier, Isabelle, CRCHUM, University of Montreal, Montreal, Quebec, Canada

Isabelle Chenier,

• Ingelfinger, Julie R., The New England Journal of Medicine, Boston, Massachusetts, United States

Julie R. Ingelfinger,

• Zhang, Shao-Ling, CRCHUM, University of Montreal, Montreal, Quebec, Canada

Shao-Ling Zhang,

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.