Tissue kallikrein attenuates salt-induced renal fibrosis by inhibition of oxidative stress.
BACKGROUND
High salt intake induces hypertension, cardiac hypertrophy, and progressive renal damage. Progressive renal injury is the consequence of a process of destructive fibrosis. Using gene transfer approach, we have shown that the tissue kallikrein-kinin system (KKS) plays an important role in protection against renal injury in several hypertensive rat models. In this study, we further investigated the effect and potential mechanisms mediated by kallikrein on salt-induced renal fibrosis.


METHODS
Adenovirus harboring the human tissue kallikrein gene was delivered intravenously into Dahl salt-sensitive (DSS) rats on a high salt diet for 4 weeks. Two weeks after gene delivery, the effect of kallikrein on renal fibrosis was examined by biochemical and histologic analysis.


RESULTS
Kallikrein gene delivery resulted in reduced blood urea nitrogen (BUN), urinary protein and albumin levels in DSS rats on a high salt diet. Expression of recombinant human tissue kallikrein was detected in the sera and urine of rats injected with the kallikrein gene. Histologic investigation showed that kallikrein gene delivery significantly reduced glomerular and tubular fibrosis scores and collagen deposition, as well as renal cell proliferation, compared to rats on a high salt diet injected with control virus. Kallikrein gene transfer significantly increased nitric oxide and cyclic guanosine monophosphate (cGMP) levels in conjunction with reduced salt-induced nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide phosphate (NADH/NADPH) oxidase activity, superoxide production, transforming growth factor-beta1 (TGF-beta1) mRNA and protein levels, and TGF-beta1 immunostaining.


CONCLUSIONS
These results indicate that tissue kallikrein protects against renal fibrosis in hypertensive DSS rats through increased nitric oxide bioavailability and suppression of oxidative stress and TGF-beta expression.
Zhang
Jenny J
JJ
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425-2211, USA.
Bledsoe
Grant
G
Kato
Kazuo
K
Chao
Lee
L
Chao
Julie
J
D000256:Adenoviridae / Q000235:genetics; D000419:Albuminuria / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001806:Blood Urea Nitrogen; D002455:Cell Division / Q000502:physiology; D024042:Collagen Type I / Q000378:metabolism; D006152:Cyclic GMP / Q000652:urine; D005355:Fibrosis; D015870:Gene Expression; D005822:Genetic Vectors; D007674:Kidney Diseases / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009097:Multienzyme Complexes / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D009569:Nitric Oxide / Q000652:urine; D018384:Oxidative Stress / Q000502:physiology*; D051381:Rats; D020303:Rats, Inbred Dahl; D017673:Sodium Chloride, Dietary / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism; D020840:Tissue Kallikreins / Q000235:genetics* / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D024042:Collagen Type I; D009097:Multienzyme Complexes; D017673:Sodium Chloride, Dietary; C508960:TGFB1 protein, human; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D013481:Superoxides; D009569:Nitric Oxide; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases; D019255:NADPH Oxidases; D020840:Tissue Kallikreins; D006152:Cyclic GMP