Abstract Body: Ischemia and reperfusion (I/R) are a leading factor in the pathogenesis of acute kidney injury (AKI) due to cardiac, lung, and kidney transplantation. The mechanisms underlying the development of I/R-induced AKI are very complex involving various genetic and humoral factors. In the present study, we tested a hypothesis that induction of acute I/R in the kidney induces the expression of intratubular renin and angiotensinogen (AGT) to generate angiotensin II (Ang II) in the kidney. Ang II activates AT₁ (AT_1a) receptors in the proximal tubules to increase the expression of Kidney Injury Molecule-1 (KIM-1), Hypoxia-Inducible Factor-1 alpha (HIF-1 alpha), Transforming Growth Factor Beta-1 (TGF-beta 1), and Fibronectin to induce kidney injury. Conversely, deletion of AT_1a receptors selectively in the proximal tubules blocks these responses and attenuates I/R-induced AKI. To test this hypothesis, wildtype (WT) and a mutant mouse model with proximal tubule-specific deletion of AT_1a receptors (PT-Agtr1a^-/-) were subject to sham or 45-min acute renal ischemia, followed by reperfusion for 24 hours or 7 days. Basal blood pressure was ~15 mmHg lower (n=7; P<0.01) while glomerular filtration rate (GFR) was ~25% higher in PT-Agtr1a^-/- mice (n=10, P<0.01). In WT mice, renin mRNA and AGT mRNA expression were markedly increased in the superficial cortex by ~81% (P<0.01) and ~64% (P<0.01), respectively, 24 h after the induction of renal I/R. KIM-1 mRNA expression was increased by >10-folds (P<0.01) and HIF-1 alpha mRNA expression was increased by ~32% (P<0.05), respectively, 24 h after the induction of renal I/R. These responses were associated with ~80% increase in TGF-beta1 mRNA expression (P<0.01) and ~6-fold increase in Fibronectin mRNA expression (P<0.01), respectively, 7 days after renal I/R induction (P<0.01). By contrast, deletion of AT_1a receptors selectively in the proximal tubules completely blocked I/R-increased renal cortical renin and AGT mRNA expression, and attenuated I/R-induced increases in KIM-1, HIF-1 alpha, TGF-beta1, Fibronectin mRNA expression in PT-Agtr1a^-/- mice (P<0.01). Moreover, GFR was significantly recovered toward control (P<0.01), while glomerular and tubulointerstitial fibrotic responses were attenuated in PT-Agtr1a^-/- mice (P<0.01), respectively. We concluded that intratubular RAS in the proximal tubules plays a key role in the development of I/R-induced AKI and may be a novel therapeutic target in preventing I/R-induced AKI.