Ischemic acute renal failure (ARF) results in the permanent loss of peritubular capillaries and predisposes the progression of chronic renal failure. The present study was undertaken to determine whether renal hypoxia, which may represent an important mediator in disease progression, is persistently exacerbated after recovery from ARF. Rats were subjected to ischemia-reperfusion injury and allowed to recover for 5 or 20 wk. Immunohistochemistry of the hypoxia-sensitive marker 2-pimonidizole at 5 wk revealed an overall increase in incorporation in the outer medullary region after recovery from ARF compared with sham-operated controls. Unilateral nephrectomy, in combination with ischemia-reperfusion injury resulted in greater 2-pimonidizole staining than that observed in the bilateral injury model. In addition, in the unilateral ischemia-nephrectomy model, proteinuria, interstitial fibrosis, and renal functional loss developed significantly faster than in the bilateral model of ARF when animals were allowed to recover for 20 wk. l-Arginine in the drinking water ( approximately 0.5 g/day) increased total renal blood flow approximately 30%, decreased pimonidizole staining, and attenuated manifestations of chronic renal disease. These data suggest that a reduction in the peritubular capillary density after ARF results in a persistent reduction in renal Po(2) and that hypoxia may play an important role in progression of chronic renal disease after ARF.