HUMAN KALLIKREIN GENE DELIVERY PROTECTS AGAINST GENTAMICIN-INDUCED NEPHROTOXICITY IN RATS

The tissue kallikrein-kinin system has been shown to play important ro les in cardiovascular and renal function. The aim of this study was to investigate potential protective effects of kallikrein gene delivery in gentamycin-induced nephrotoxicity. Rats were injected subcutaneousl y with gentamycin daily for 10 to 14 days. Adenovirus, Ad.CMV-cHK carr ying the human tissue kallikrein gene or Ad.CMV-LacZ carrying the beta -galactosidase gene under the control of the cytomegalovirus pro meter , were delivered intravenously on the first day of gentamycin administ ration. The expression of human tissue kallikrein mRNA was identified in the kidney, aorta, heart and liver and immunoreactive human kallikr ein levels were measured in the serum and urine of rats receiving kall ikrein gene delivery. Adenovirus-mediated kallikrein gene delivery sig nificantly increased the renal blood flow, glomerular filtration rates , and urine flow while it attenuated renal tubular damage, cellular ne crosis, lumenal protein casts and reduced ventricular weight and cardi omyocyte size. Kallikrein gene delivery caused a decrease in blood ure a nitrogen levels and increases in urinary kinin and nitrite/nitrate l evels. This study shows that kallikrein gene delivery exhibits protect ion against gentamycin-induced nephrotoxicity, and raises the potentia l for kallikrein gene therapy to treat drug-induced renal diseases.