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.
Murakami
H
H
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, USA.
Yayama
K
K
Chao
L
L
Chao
J
J
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D001483:Base Sequence; D001806:Blood Urea Nitrogen; D006332:Cardiomegaly / Q000517:prevention & control; D017931:DNA Primers / Q000235:genetics; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors; D005839:Gentamicins / Q000633:toxicity*; D006801:Humans; D007150:Immunohistochemistry; D007610:Kallikreins / Q000235:genetics* / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007700:Kinetics; D008297:Male; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D000900:Anti-Bacterial Agents; D017931:DNA Primers; D005839:Gentamicins; D012333:RNA, Messenger; D007610:Kallikreins