The activation of the intrarenal renin-angiotensin system plays an important role in the pathogenesis of renal ischemia-reperfusion injury, but the underlying cellular and signaling mechanisms remain incompletely understood. In the present study, we tested the hypothesis that conditional knockout of AT1a receptors selectively in the proximal tubules attenuates renal ischemia-reperfusion injury in mice. Three groups (n=5-8/per group) of adult male C57BL/6J (WT), global AT1a receptor-deficient (AT1a-KO), and conditional proximal tubule-specific AT1a-KO mice (PT-AT1a-KO) were subjected to sham surgery or 30 min unilateral left kidney ischemia, followed by reperfusion for 24 h or 7 days, respectively. Under basal conditions, systolic blood pressure was 25 ± 3 mmHg lower in global AT1a-KO (p<0.01) or 13 ± 3 mmHg lower in PT-AT1a-KO mice (p<0.05), respectively. Systolic blood pressure, 24 h urine and urinary sodium excretion were not significantly altered in all strains 24 h or 7 days after renal ischemia-reperfusion. Kidney wt. to body wt. ratio, but not heart wt. to body wt. ratio, was significantly increased in both AT1a-KO and PT-AT1a-KO mice (p<0.05). Renal ischemia-reperfusion injury was assessed by Masson Trichrome staining and compared between WT, AT1a-KO and PT-AT1a-KO mice. No significant glomerular, tubulointerstital, and peri-vascular fibrotic responses were observed in sham controls of all strains. However, significant fibrotic responses were observed in the glomeruli, cortical tubulointerstitial and peri-vascular tissues in WT mice 24 h or 7 days after renal ischemia-reperfusion (p<0.01). Surprisingly, however, glomerular, tubulointerstital, and peri-vascular fibrotic responses were significantly worsen, rather than improved, in global AT1a-KO mice (p<0.01). By comparison, conditional deletion of AT1a receptors selectively in the proximal tubules markedly attenuated glomerular, tubulointerstital, and peri-vascular fibrotic responses in PT-AT1a-KO mice 24 h or 7 days after renal ischemia-reperfusion (p<0.01). Our results suggest that AT1a receptors in the proximal tubule play an important role in the pathogenesis of renal ischemia-reperfusion injury, and thus may represent a therapeutic target in the future.
Proximal Tubule CD73 Is Critical in Renal Ischemia-Reperfusion Injury Protection
