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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-specific deletion of angiotensinogen (Agt; RT-Agt-/-) in both Akita and streptozotocin (STZ)-induced mouse model of diabetes. Both Akita RT-Agt-/- and STZ-RT-Agt-/- mice exhibited significant attenuation of glomerular hyperfiltration, urinary albumin/creatinine ratio, glomerulomegaly and tubular injury. Urinary Agt, Angiotensin II (Ang II) and oxidative stress were decreased in Akita RT-Agt-/- mice cf. Akita mice. Moreover, thickened glomerular basement membranes, podocyte foot process effacement and podocyte loss were ameliorated in Akita RT-Agt-/- mice cf. Akita mice. Mechanistically, intra-vital microscopy revealed that attenuation of glomerular hyperfiltration in Akita RT-Agt-/- mice was mediated via efferent arteriole (EA) vasodilation and afferent arteriole (AA) vasoconstriction. The AA vasoconstriction was regulated, at least partially, through tubulo-glomerular feedback by down-regulation of sodium-glucose co-transporter 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, losartan and apocynin inhibited SGLT2 expression in immortalized human renal proximal tubular cells. These findings suggest targeting the iRAS may constitute effective treatment for DKD., (© 2025 by the American Diabetes Association.)