Chao Julie, Li Huey-Jiun, Yao Yu-Yu, Shen Bo, Gao Lin, Bledsoe Grant, Chao Lee
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
Hypertension. 2007 Mar;49(3):490-7. doi: 10.1161/01.HYP.0000255925.01707.eb. Epub 2007 Jan 15.
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-beta1 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-beta1 expression, and mitogen-activated protein kinase activation.
肾脏疾病的进展呈现出几个特征，包括蛋白尿、细胞凋亡、炎症和纤维化。在本研究中，我们调查了长期输注激肽对Dahl盐敏感大鼠盐诱导的肾损伤的保护作用。给Dahl盐敏感大鼠喂食高盐饮食2周，然后通过皮下植入的微型泵以500 ng/h的速度输注缓激肽3周。输注激肽减轻了盐诱导的肾功能损害，表现为蛋白尿、血清肌酐和血尿素氮水平降低，而对血压无明显影响。形态学分析表明，给予激肽可减少盐诱导的肾小球硬化、肾小管扩张、管腔内蛋白管型形成和小叶间动脉厚度。激肽还显著降低了I型、III型和IV型胶原蛋白的沉积及其mRNA水平。此外，激肽减少了间质单核细胞/巨噬细胞的积聚，以及肾小管细胞凋亡和半胱天冬酶-3活性。激肽对肾损伤的保护作用与肾一氧化氮水平升高、烟酰胺腺嘌呤二核苷酸/烟酰胺腺嘌呤二核苷酸磷酸氧化酶活性降低和超氧化物生成减少有关。激肽对氧化应激的抑制伴随着转化生长因子-β1蛋白和mRNA水平的降低，以及丝裂原活化蛋白激酶磷酸化的减少。这是第一项证明输注激肽可通过抑制氧化应激、转化生长因子-β1表达和丝裂原活化蛋白激酶激活来抑制细胞凋亡、炎症和纤维化，从而在不降低血压的情况下直接保护免受盐诱导的肾损伤的研究。
