Role of caspases on cell death, inflammation, and cell cycle in glycerol-induced acute renal failure

被引:131
作者
Homsi, E [1 ]
Janino, P [1 ]
de Faria, JBL [1 ]
机构
[1] Univ Estadual Campinas, Sch Med Sci, Dept Med, Div Nephrol, BR-13083887 Campinas, SP, Brazil
基金
巴西圣保罗研究基金会;
关键词
acute renal failure; apoptosis; inflammation; caspases;
D O I
10.1038/sj.ki.5000315
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
Caspases are the main executioners of apoptosis as well as interleukin (IL)-1 beta and IL-18 conversion to active forms. They are activated after acute kidney injuries. In this study, we evaluated the importance of the caspase family in the pathogenesis and recovery of glycerol-induced acute renal failure in rats (Gly-ARF). Rats were treated with pan-caspase or selective caspase 1 and 3 inhibitors at the moment we injected glycerol. Renal function, renal histology ( HE), transferase- mediated deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling staining for apoptosis, leukocytes infiltration ( immunohistochemistry), renal expression of IL-1 beta and IL-18 ( immunohistochemistry and Western blot), tubular regeneration ( 5-bromo-2'-deoxyuridine ( BrdU) incorporation), and P27(Kip) expression ( Western blot) were evaluated at appropriate times. All inhibitors reduced the renal function impairment. Pan-caspase and caspase-3 inhibitors reduced cellular death ( necrosis and apoptosis) 24 h after Gly-ARF. All caspases inhibitors reduced macrophages infiltration. The expression of total IL-1 beta was enhanced in Gly-ARF, but the active IL-1 beta and IL-18 forms were abolished in pan-caspase treated rats. Caspase-1 inhibitor attenuated Gly-ARF but not tubular injury suggesting glomerular hemodynamic improvement. There was striking regenerative response 48 h after Gly-ARF characterized by enhanced BrdU incorporation and reduced expression of p27(Kip.) This response was not blunted by caspases inhibition. Our findings demonstrate that caspases participate in important pathogenic mechanisms in Gly-ARF such as inflammation, apoptosis, vasoconstriction, and tubular necrosis. The early inhibition of caspases attenuates these mechanisms and reduces the renal function impairment in Gly-ARF.
引用
收藏
页码:1385 / 1392
页数:8
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