Chatterjee P K, Brown P A, Cuzzocrea S, Zacharowski K, Stewart K N, Mota-Filipe H, McDonald M C, Thiemermann C
Department of Experimental Medicine and Nephrology, The William Harvey Research Institute, and the Royal London School of Medicine and Dentistry, London, England, United Kingdom.
Kidney Int. 2001 Jun;59(6):2073-83. doi: 10.1046/j.1523-1755.2001.00722.x.
Activation of the cysteine protease calpain has been implicated in renal ischemia/reperfusion (I/R) injury. The aim of this study was to investigate the effects of calpain inhibitor-1 (Cal I-1) in an in vivo model of renal I/R injury.
Male Wistar rats were administered Cal I-1 (10 mg/kg, IP) 30 minutes before undergoing bilateral renal ischemia (45 minutes) followed by reperfusion (6 hours). Plasma concentrations of urea, creatinine, Na(+), gamma-glutamyl transferase (gamma GT), aspartate aminotransferase (AST) and urinary Na(+), glutathione S-transferase (GST), and N-acetyl-beta-D-glucosaminidase (NAG) were measured for the assessment of renal dysfunction and I/R injury. Creatinine clearance (C(Cr)) and fractional excretion of Na(+) (FE(Na)) were used as indicators of glomerular and tubular function, respectively. Kidney myeloperoxidase (MPO) activity and malondialdehyde (MDA) levels were measured for assessment of neutrophil infiltration and lipid peroxidation, respectively. Renal sections were used for histologic grading of renal injury and for immunohistochemical localization of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2).
Cal I-1 significantly reduced I/R-mediated increases in urea, creatinine, gamma GT, AST, NAG, and FE(Na) and significantly improved C(Cr). Cal I-1 also significantly reduced kidney MPO activity and MDA levels. Cal I-1 also reduced histologic evidence of I/R-mediated renal damage and caused a substantial reduction in the expression of iNOS and COX-2, both of which involve activation of nuclear factor-kappa B (NF-kappa B).
: These results suggest that Cal I-1 reduces the renal dysfunction and injury associated with I/R of the kidney. We suggest that the mechanism could involve the inhibition of I/R-mediated activation of NF-kappa B.
半胱氨酸蛋白酶钙蛋白酶的激活与肾脏缺血/再灌注（I/R）损伤有关。本研究的目的是在肾脏I/R损伤的体内模型中研究钙蛋白酶抑制剂-1（Cal I-1）的作用。
雄性Wistar大鼠在双侧肾脏缺血（45分钟）后再灌注（6小时）前30分钟给予Cal I-1（10毫克/千克，腹腔注射）。测量血浆中尿素、肌酐、Na⁺、γ-谷氨酰转移酶（γGT）、天冬氨酸转氨酶（AST）以及尿液中Na⁺、谷胱甘肽S-转移酶（GST）和N-乙酰-β-D-氨基葡萄糖苷酶（NAG）的浓度，以评估肾功能障碍和I/R损伤。肌酐清除率（C(Cr)）和Na⁺分数排泄率（FE(Na)）分别用作肾小球和肾小管功能的指标。测量肾脏髓过氧化物酶（MPO）活性和丙二醛（MDA）水平，分别用于评估中性粒细胞浸润和脂质过氧化。肾脏切片用于肾脏损伤的组织学分级以及诱导型一氧化氮合酶（iNOS）和环氧化酶-2（COX-2）的免疫组织化学定位。
Cal I-1显著降低了I/R介导的尿素、肌酐、γGT、AST、NAG和FE(Na)的升高，并显著改善了C(Cr)。Cal I-1还显著降低了肾脏MPO活性和MDA水平。Cal I-1还减少了I/R介导的肾脏损伤的组织学证据，并导致iNOS和COX-2的表达大幅降低，这两者都涉及核因子-κB（NF-κB）的激活。
这些结果表明Cal I-1可减轻与肾脏I/R相关的肾功能障碍和损伤。我们认为其机制可能涉及抑制I/R介导的NF-κB激活。
