This study tested the hypothesis that P2Y12 receptor blockade with clopidogrel preserves renal autoregulatory ability during angiotensin II (Ang II)-induced hypertension. Clopidogrel was administered orally to male Sprague-Dawley rats chronically infused with Ang II. Following 14 days of treatment, whole kidney autoregulation of renal blood flow was assessed in vivo in pentobarbital anesthetized rats using an ultrasonic flow probe placed around the left renal artery. In Ang II-vehicle treated rats, decreasing arterial pressure over a range from 160-100 mmHg resulted in a 25±5% decrease in renal blood flow demonstrating significant loss of autoregulation with an autoregulatory index (AI) of 0.66±0.15. However, clopidogrel treatment preserved autoregulatory behavior in Ang II rats to levels indistinguishable from normotensive sham rats (AI, 0.04±0.14). Compared to normotensive sham-vehicle rats, Ang II infusion increased renal CD-3 positive T-cell infiltration by 66±6%, induced significant thickening of the preglomerular vessels, glomerular basement membrane (GBM), increased glomerular collagen I deposition, tubulo-interstitial fibrosis and damage to proximal tubular brush border and increased protein excretion. Clopidogrel significantly reduced renal infiltration of T-cells by 39±9%, prevented interstitial artery thickening, Ang II-induced damage to GBM, deposition of collagen I, and tubulo-interstitial fibrosis, despite maintenance of hypertension. These data demonstrate that systemic P2Y12 receptor blockade with clopidogrel protects against impairment of autoregulatory behavior and renal vascular injury in Ang II-induced hypertension possibly by reducing renal T-cell infiltration.