Apoptosis has been shown to contribute to the development of acute and chronic renal failure. The anti-apoptotic action of the HO system may represent an important protective mechanism in kidney pathology. We examined whether the lack of HO-1 would influence apoptosis in clipped kidneys of 2K1C rats. Five-day-old Sprague-Dawley rats were injected in the left ventricle with 5x10₉ cfu/mL of retrovirus, containing rat HO-1 antisense (LSN-RHO-1-AS) or control retrovirus (LXSN). After three months, a 0.25 mm U-shaped silver clip was placed around the left renal artery. Animals were sacrificed three weeks later. Clipping the renal artery in LSN-RHO-1-AS rats did not result in increased HO-1 expression. In contrast to LXSN animals, 2K1C LSN-RHO-1-AS rats showed increased expression of COX-2 and higher 3-NT content as well as increased expression of the pro-apoptotic protein Apaf-1 and caspase-3 activity. Clipping the renal artery in LXSN rats resulted in increased expression of the anti-apoptotic proteins Bcl-2 and Bcl-xl while clipping the renal artery in LSN-RHO-1-AS rats did not change Bcl-2 levels and decreased the levels of Bcl-xl. Treatment of LSN-RHO-1-AS rats with CoPP resulted in induction of renal HO-1, which was accompanied by decreases in blood pressure, COX-2, 3-NT, and caspase-3 activity, and increased expression of anti-apoptotic molecules (Bcl-2, Bcl-xl, Akt and p-Akt) in the clipped kidneys. These findings underscore the prominent role of HO-1 in counteracting apoptosis in this 2K1C renovascular hypertension model.