Protective effects of low-dose carbon monoxide against renal fibrosis induced by unilateral ureteral obstruction.
Protective effects of low-dose carbon monoxide against renal fibrosis induced by unilateral ureteral obstruction.
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DOI：
10.1152/ajprenal.00306.2007
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发表时间：
2008-03
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影响因子：
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通讯作者：
Lin Wang;Ji‐Yang Sophie Lee;J. Kwak;Yanjuan He;S. I. Kim;Mary E. Choi
中科院分区：
文献类型：
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作者：
Lin Wang;Ji‐Yang Sophie Lee;J. Kwak;Yanjuan He;S. I. Kim;Mary E. Choi
肾小管间质纤维化是导致终末期肾衰竭的慢性进行性肾病的标志。血红素加氧酶活性的内源性产物一氧化碳（CO）已被证明对组织损伤发挥细胞保护作用。在这里，我们探讨了外源性低剂量CO在单侧输尿管梗阻（UUO）诱导的肾纤维化的体内模型中的作用，并检查CO是否可以保护肾损伤。小鼠UUO导致细胞外基质（ECM）沉积增加，并在4至7天内导致肾小管间质纤维化。然而，暴露于低剂量CO的小鼠肾脏在UUO后显著减少了ECM沉积。此外，低剂量CO治疗抑制UUO后肾脏中α-平滑肌肌动蛋白（α-SMA）和主要ECM蛋白（1型胶原和纤连蛋白）的诱导。相反，CO处理的这些抗纤维化作用在携带Mkk 3无效突变的小鼠中被消除，表明MKK 3信号传导通路参与介导CO作用。此外，体外CO暴露显著抑制TGF-β 1诱导的肾近端小管上皮细胞中α-SMA、胶原和纤连蛋白的表达。我们的研究结果表明，低剂量CO通过MKK 3通路发挥保护作用，抑制梗阻性肾病肾纤维化的发展。
Tubulointerstitial fibrosis is a hallmark of chronic progressive kidney disease leading to end-stage renal failure. An endogenous product of heme oxygenase activity, carbon monoxide (CO), has been shown to exert cytoprotection against tissue injury. Here, we explored the effects of exogenous administration of low-dose CO in an in vivo model of renal fibrosis induced by unilateral ureteral obstruction (UUO) and examined whether CO can protect against kidney injury. UUO in mice leads to increased extracellular matrix (ECM) deposition and tubulointerstitial fibrosis within 4 to 7 days. Kidneys of mice exposed to low-dose CO, however, had markedly reduced ECM deposition after UUO. Moreover, low-dose CO treatment inhibited the induction of alpha-smooth muscle actin (alpha-SMA) and major ECM proteins, type 1 collagen and fibronectin, in kidneys after UUO. In contrast, these anti-fibrotic effects of CO treatment were abrogated in mice carrying null mutation of Mkk3, suggesting involvement of the MKK3 signaling pathway in mediating the CO effects. Additionally, in vitro CO exposure markedly inhibited TGF-beta(1)-induced expression of alpha-SMA, collagen, and fibronectin in renal proximal tubular epithelial cells. Our findings suggest that low-dose CO exerts protective effects, via the MKK3 pathway, to inhibit development of renal fibrosis in obstructive nephropathy.