Unilateral ureteral obstruction is characterized by decreases in renal function, increased interstitial fibrosis, tubular apoptosis, and cellular infiltration. It has been suggested that inhibition of tubular apoptosis may protect against renal damage in obstruction. We have recently developed a series of peptides which are concentrated in the inner mitochondrial membrane and prevent cell death. These peptides are also active in vivo, in myocardial infraction, ischemic brain injury and amyotrophic lateral sclerosis models. We therefore used SS-31, a prototype of these peptides, and assessed its effects on renal damage and oxidative stress in a 14-day obstruction model. SS-31 [1 or 3 mg/kg] or saline was given one day prior to and throughout the 14 days of obstruction. Kidneys were harvested and assessed for apoptosis [TUNEL, caspase 3 expression], fibrosis [trichrome staining], macrophage infiltration and fibroblast expression [immunoperoxidase] and oxidative damage [8-OH deoxyguanosine and heme oxygenase-1 expression], cytokines and signaling pathways [TGF-, CCR-1, P38-MAPK, NFB]. SS-31 significantly attenuated the effects of obstruction on all aspects of renal damage which were examined, with both the 1 mg/kg and 3 mg/kg doses showing efficacy. We noted increased oxidative stress in obstruction, which was also attenuated by SS-31 treatment. Signaling via NF B and p38 MAP Kinase pathways were both affected by SS-31 treatment. This study provides proof of concept that peptides which protect mitochondria in vitro can provide protection from renal damage in a UUO model. The mechanism by which protection is afforded requires further studies both in vitro and in vivo.