H Murakami1, K Yayama, J Chao, L Chao. 1. Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston 29425-2211, USA.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: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. METHODS: Adenovirus (Ad.RSV-ANP) carrying the humanANP 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. RESULTS: 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 ureanitrogen levels. Histological evaluations revealed that ANP delivery attenuated gentamycin-induced renal tubular damage, cellular necrosis, and lumenal protein casts. The expression of humanANP mRNA was identified in rat kidney, heart, aorta and liver. Immunoreactive humanANP 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. CONCLUSIONS: 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.