Published Online
on January 15, 2007

A more recent version of this article appeared on March 1, 2007

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Submitted on August 23, 2006
Revised on September 15, 2006

Kinin Infusion Prevents Renal Inflammation, Apoptosis, and Fibrosis via Inhibition of Oxidative Stress and Mitogen-Activated Protein Kinase Activity

Julie Chao; Huey-Jiun Li; Yu-Yu Yao; Bo Shen; Lin Gao; Grant Bledsoe; and Lee Chao^*

From the Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston.

^* To whom correspondence should be addressed. E-mail: chaol{at}musc.edu.

Abstract--The progression of renal disease displays several characteristics, including proteinuria, apoptosis, inflammation, and fibrosis. In this study, we investigated the effect of long-term infusion of kinin in protection against salt-induced renal damage in Dahl salt-sensitive rats. Dahl salt-sensitive rats were fed a high-salt diet for 2 weeks and were then infused with bradykinin (500 ng/h) via subcutaneously implanted minipumps for 3 weeks. Kinin infusion attenuated salt-induced impaired renal function as evidenced by reduced proteinuria, serum creatinine, and blood urea nitrogen levels without apparent effect on blood pressure. Morphological analysis indicated that kinin administration reduced salt-induced glomerular sclerosis, tubular dilatation, luminal protein cast formation, and interlobular arterial thickness. Kinin also significantly lowered collagen I, III, and IV deposition and their mRNA levels. Moreover, kinin reduced interstitial monocyte/macrophage accumulation, as well as tubular cell apoptosis and caspase-3 activity. Protection of renal injury by kinin was associated with increased renal NO levels and reduced nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide phosphate oxidase activities and superoxide generation. Suppression of oxidative stress by kinin was accompanied by reduced transforming growth factor-1 protein and mRNA levels, as well as decreased phosphorylation of mitogen-activated protein kinases. This is the first study to demonstrate that kinin infusion can directly protect against salt-induced renal injury without blood pressure reduction by inhibiting apoptosis, inflammation, and fibrosis via suppression of oxidative stress, transforming growth factor-1 expression, and mitogen-activated protein kinase activation.

Key words: kinin • fibrosis • kidney • oxidative stress • inflammation • apoptosis • mitogen-activated protein kinases

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