Bradykinin decreases plasminogen activator inhibitor-1 expression and facilitates matrix degradation in the renal tubulointerstitium under angiotensin-converting enzyme blockade
Bradykinin decreases plasminogen activator inhibitor-1 expression and facilitates matrix degradation in the renal tubulointerstitium under angiotensin-converting enzyme blockade
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DOI：
10.1097/01.asn.0000136132.20189.95
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发表时间：
2004-09-01
影响因子：
13.6
通讯作者：
Suzuki, H
中科院分区：
文献类型：
--
作者：
Okada, H;Watanabe, Y;Suzuki, H
大量实验和临床研究支持血管紧张素转换酶抑制剂(ACEI)和血管紧张素II 1型受体阻滞剂(ARB)化合物可减轻肾脏纤维化的观点。纤维化可以通过抑制基质形成或促进基质降解来减轻。在这项研究中，测试了ACEI和ARB类药物促进肾脏基质降解的能力。在小鼠模型系统中，环孢素A(CsA)治疗特定时间导致肾脏间质基质沉积。然后停止CsA，并启动实验程序来研究基质降解。苯那普利是一种血管紧张素转换酶抑制剂，通过肾小管上皮细胞上的缓激肽B2受体促进基质降解，而血管紧张素Ⅱ受体拮抗剂CGP-48933则不能。在ACE阻断的CsA肾病模型中，肾小管上皮细胞纤溶酶原激活物抑制物-1(PAI-1)的表达降低，可能导致纤溶酶原通过纤溶酶原激活剂转化为纤溶酶，继而激活基质金属蛋白酶。通过测量肾脏中的纤溶酶活性、胶原酶活性和基质金属蛋白酶活性，证实了这些发现。在体外刺激的肾小管上皮细胞中，BK抑制PAI-1基因的表达。所有这些结果表明，ACEI可以通过BK降低PAI-1的表达，从而通过激活降解酶来减少间质基质的沉积，从而促进基质的降解。
A number of experimental and clinical investigations support the notion that angiotensin-converting enzyme inhibitor (ACEi) and angiotensin II type 1 receptor blocker (ARB) compounds attenuate renal fibrosis. Fibrosis can be attenuated by either suppressing matrix formation or facilitating matrix degradation. In this study, drugs of ACEi and ARB classes were tested for their ability to facilitate matrix degradation in the kidney. A murine model system in which cyclosporin A (CsA) treatment for a specified period caused interstitial matrix deposition in the kidney was used. CsA was then discontinued, and experimental procedures were initiated to investigate matrix degradation. Benazepril, an ACEi, facilitated matrix degradation via the bradykinin (BK) B2 receptor on tubular epithelial cells in the kidney, whereas CGP-48933, an ARB, did not. In this murine model of CsA nephropathy under ACE blockade, plasminogen activator inhibitor-1 (PAI-1) expression was decreased in tubular epithelial cells, possibly leading to conversion of plasminogen to plasmin by plasminogen activator and subsequent activation of matrix metalloproteinases. These findings were confirmed in this study by measurements of plasmin activity, collagenolytic activity, and matrix metalloproteinase activities in the kidneys. In tubular epithelial cells stimulated in vitro, BK suppressed PAI-1 gene expression. All of these results suggest that ACEi can decrease PAI-1 expression via BK, thereby facilitating matrix degradation via activation of degradative enzymes to reduce interstitial matrix deposition.