Gentamycin-induced Nephrotoxicity Research Articles

Atrial natriuretic peptide gene delivery attenuates gentamycin-induced nephrotoxicity in rats.

Atrial natriuretic peptide (ANP) is a cardiac hormone which exerts potent natriuretic and vasorelaxant activities. The aim of this study is to investigate potential protective effects of ANP gene delivery in gentamycin-induced nephrotoxicity. Adenovirus (Ad.RSV-ANP) carrying the human ANP gene or carrying the LacZ gene (Ad.RSV-LacZ) under the control of the Rous sarcoma virus promoter were delivered intravenously on the first day of gentamycin administration. Sprague Dawley rats were injected subcutaneously with gentamycin daily for 10 days. A single systemic injection of Ad.RSV-ANP at a dose of 1.2x10(10) pfu results in a significant increase in urine excretion, water intake, urinary sodium and potassium excretion. Adenovirus-mediated ANP gene delivery significantly increased renal blood flow, glomerular filtration rates and urine flow as well as attenuated the elevation of blood urea nitrogen levels. Histological evaluations revealed that ANP delivery attenuated gentamycin-induced renal tubular damage, cellular necrosis, and lumenal protein casts. The expression of human ANP mRNA was identified in rat kidney, heart, aorta and liver. Immunoreactive human ANP was detected in the heart and kidney of rats injected with Ad.RSV-ANP but not in rats injected with Ad.RSV-LacZ. Cyclic GMP levels in the kidney were significantly increased in rats receiving ANP gene delivery. This study shows that ANP gene delivery exhibits protection against gentamycin-induced nephrotoxicity and raises the potential to use ANP gene therapy for the treatment of drug-induced renal failure.

Human kallikrein gene delivery protects against gentamycin-induced nephrotoxicity in rats

The tissue kallikrein-kinin system has been shown to play important roles 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 subcutaneously with gentamycin daily for 10 to 14 days. Adenovirus, Ad.CMV-cHK carrying the human tissue kallikrein gene or Ad.CMV-LacZ carrying the beta-galactosidase gene under the control of the cytomegalovirus promoter, were delivered intravenously on the first day of gentamycin administration. The expression of human tissue kallikrein mRNA was identified in the kidney, aorta, heart and liver and immunoreactive human kallikrein levels were measured in the serum and urine of rats receiving kallikrein gene delivery. Adenovirus-mediated kallikrein gene delivery significantly increased the renal blood flow, glomerular filtration rates, and urine flow while it attenuated renal tubular damage, cellular necrosis, lumenal protein casts and reduced ventricular weight and cardiomyocyte size. Kallikrein gene delivery caused a decrease in blood urea nitrogen levels and increases in urinary kinin and nitrite/nitrate levels. This study shows that kallikrein gene delivery exhibits protection against gentamycin-induced nephrotoxicity, and raises the potential for kallikrein gene therapy to treat drug-induced renal diseases.