The tissue kallikrein-kinin system is important in regulating cardiovascular and renal function, and dysregulation of the system has been implicated in heart and kidney pathologies. These findings suggest that if balance can be restored to the kallikrein-kinin axis, then associated disease progression may be attenuated. To test this hypothesis, recombinant adeno-associated virus (rAAV)-mediated human tissue kallikrein (HK) expression was induced in a rodent model of chronic renal failure involving 5/6 nephrectomy. rAAV-HK treatment attenuated the rise in blood pressure, glomerular sclerosis, and tubulointerstitial injury observed in this model. rAAV-HK treatment also attenuated renal function decline as measured by urinary microalbumin, osmolarity and cGMP levels. RT-PCR analysis showed that rAAV-HK treated rats had higher levels of bradykinin-B 2 receptor (B 2 R) and dopamine D 1 -like receptor mRNAs. In contrast, angiotensin II receptor 1, endothelin ET A receptor, and vasopressin V 2 receptor mRNAs were markedly downregulated in kidneys from HK-treated rats. Bradykinin induced similar changes in receptor levels and prevented TGF-β1-induced tubulointerstitial fibrosis. The effects of bradykinin could be reversed by the B 2 R antagonist HOE-140. Together, these findings suggest that restoration of the kallikrein-kinin system reduces kidney injury and protects renal function in 5/6 nephrectomized rats via changes in the expression and activation of G-protein coupled receptors including B 2 R.