Renal Tubule–Specific Angiotensinogen Deletion Attenuates SGLT2 Expression and Ameliorates Diabetic Kidney Disease in Murine Models of Type 1 Diabetes

Abstract

The role of the intrarenal renin-angiotensin system (iRAS) in diabetic kidney disease (DKD) progression remains unclear. In this study, we generated mice with renal tubule (RT)-specific deletion of angiotensinogen (Agt ;RT-Agt-/-) in both Akita and a streptozotocin (STZ)-induced mouse model of diabetes. Both Akita RT-Agt-/- and STZ-RT-Agt-/- mice exhibited significant attenuation of glomerular hyperfiltration, urinary albumin–to–creatinine ratio, glomerulomegaly, and tubular injury. Urinary Agt, angiotensin II (Ang II), and oxidative stress were decreased in Akita RT-Agt-/- mice compared with Akita mice. Moreover, thickened glomerular basement membranes, podocyte foot process effacement, and podocyte loss were ameliorated in Akita RT-Agt-/- mice compared with Akita mice. Mechanistically, intravital microscopy revealed that attenuation of glomerular hyperfiltration in Akita RT-Agt-/- mice was mediated via efferent arteriole vasodilation and afferent arteriole (AA) vasoconstriction. The AA vasoconstriction was regulated, at least partially, through tubuloglomerular feedback by downregulation of sodium–glucose cotransporter 2 (SGLT2) expression in renal proximal tubules. The renal protective effect of iRAS inactivation in Akita RT-Agt-/- mice was more evident than in Akita mice treated with RAS blockers. In vitro, Ang II stimulated and losartan and apocynin inhibited SGLT2 expression in immortalized human renal proximal tubular cells. These findings suggest targeting the iRAS mayconstitute effective treatment of DKD.