Conditional transgenic mice that express one of the HIV-1 accessory genes, vpr, selectively in podocytes using a podocin-promoter and Tet-on system develop renal injuries similar to those of patients with HIV-associated nephropathy (HIVAN). We have shown that a heminephrectomy accelerates podocyte injury, which is alleviated by angiotensin II (AngII) type 1 receptor blocker (ARB). The current study further explores the role of AngII in the genesis of HIVAN in this murine model. Heavy proteinuria was observed at 1 week after the initiation of doxycycline administration to induce vpr expression in podocytes. Severe morphological and phenotypical changes in the podocytes were observed at 2 weeks, together with extensive glomerulosclerosis. Norepinephrine infusion, instead of AngII, increased the systemic blood pressure to the same level as that achieved using AngII. However, albuminuria and glomerular injury were modest in norepinephrine-infused mice. Treatment with an ARB, olmesartan, almost completely inhibited glomerular injury. In contrast, lowering the blood pressure with a vasodilator, hydralazine, partially decreased albuminuria but did not produce any histological changes. AngII infusion alone without doxycycline resulted in a lower level of albuminuria and minimal histological changes. These data demonstrate that excessive AngII accelerates vpr-induced podocyte injury in a mouse model of HIVAN.