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Kidney Int. 2004 Aug;66(2):722-32.

Tissue kallikrein attenuates salt-induced renal fibrosis by inhibition of oxidative stress.

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  • 1Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425-2211, USA.

Abstract

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.

CONCLUSION:

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.

PMID:
15253727
[PubMed - indexed for MEDLINE]
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