(VP092) RENAL TUBULE-SPECIFIC ANGIOTENSINOGEN KNOCKOUT AMELIORATES DIABETIC KIDNEY DISEASE IN TYPE 1 DIABETIC AKITA MICE

Background: While intensive therapy with insulin and renin-angiotensin system (RAS) blockers are effective in retarding diabetic kidney disease (DKD) progression, they do not cure it. Angiotensinogen (AGT, the sole precursor of all angiotensin) expression is up-regulated in renal proximal tubules (RPTs) of animals and patients with diabetes. However, the role of intrarenal RAS in DKD progression is not well understood.

METHODS AND RESULTS:
Akita renal tubule (RT)-specific Agt knock-out (Akita AgtRT KO) mice were generated by crossbreeding Akita with AgtRT KO mice using Pax8-Cre (generated by crossbreeding male Agt floxed mice with female RT-specific Cre deleter (Pax8-Cre) mice and studied at the age of 10 to 20 weeks. Physiological and kidney morphological changes were assessed. Immunostaining on kidney sections, Western blot (WB) and real-time qPCR (RT-qPCR) of isolated RPTs were employed to assess protein and gene expression.

RT-Agt deletion did not significantly affect systolic blood pressure but normalized glomerular filtration rate (reversal in hyperfiltration) in Akita AgtRT KO mice vs Akita mice. Fasting blood glucose was lower in Akita AgtRT KO mice vs Akita mice. Glomerular tuft volume, proximal tubular cell size, tubular luminal dilation, tubular injury score, kidney weight/tibial length and urinary albumin-creatinine ratio (ACR) were significantly increased in Akita mice but attenuated in Akita AgtRT KO mice. Sodium-glucose cotransporter 2 (SGLT2) protein and gene expression in RPT was significantly decreased in Akita AgtRT KO mice vs Akita mice.

Conclusion: RT-deletion of Agt attenuated blood glucose, glomerular hyperfiltration, ACR, kidney injury and SGLT2 expression in Akita mice, indicating that intrarenal RAS activation aggravates DKD progression in diabetes.