In deoxycorticosterone acetate (DOCA)-salt hypertension, renal kallikrein levels are increased and may play a protective role in renal injury. We investigated the effect of enhanced kallikrein levels on kidney remodeling of DOCA-salt hypertensive rats by systemic delivery of adenovirus containing human tissue kallikrein gene. Recombinant human kallikrein was detected in the urine and serum of rats after gene delivery. Kallikrein gene transfer significantly decreased DOCA-salt-induced proteinuria, glomerular sclerosis, tubular dilatation and lumenal protein casts. Sirius red staining showed that kallikrein gene transfer reduced renal fibrosis, which was confirmed by decreased collagen I and fibronectin levels. Furthermore, kallikrein gene delivery diminished myofibroblast accumulation in the interstitium of the cortex and medulla, as well as transforming growth factor (TGF)-1 immunostaining in glomeruli. Western blot analysis and ELISA verified the decrease in immunoreactive TGF-1 levels. Kallikrein gene transfer also significantly reduced kidney weight, glomerular size, as well as proliferating tubular epithelial cells and macrophages/monocytes. Reduction of proliferation and hypertrophy was associated with reduced levels of the cyclin-dependent kinase inhibitor p27^Kip1, and the phosphorylation of c-jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK). The protective effects of kallikrein were accompanied by increased urinary nitrate/nitrite (NOx) and cGMP levels, and suppressed superoxide formation. These results indicate that kallikrein protects against mineralocorticoid-induced renal fibrosis, glomerular hypertrophy and renal cell proliferation via inhibition of oxidative stress, JNK/ERK activation and p27^Kip1 and TGF-1 expression