Department of Internal Medicine, Kyungpook National University School of Medicine, 50 Samdeok-2ga, Jung-gu, Daegu 700-721, South Korea.
J Am Soc Nephrol. 2012 Jan;23(1):73-85. doi: 10.1681/ASN.2011010048. Epub 2011 Nov 3.
Upregulation of clusterin occurs in several renal diseases and models of nephrotoxicity, but whether this promotes injury or is a protective reaction to injury is unknown. Here, in the mouse unilateral ureteral obstruction model, obstruction markedly increased the expression of clusterin, plasminogen activator inhibitor-1 (PAI-1), type I collagen, and fibronectin. Compared with wild-type mice, clusterin-deficient mice exhibited higher levels of PAI-1, type I collagen, and fibronectin and accelerated renal fibrosis in response to obstruction. In cultured rat tubular epithelium-like cells, adenovirus-mediated overexpression of clusterin inhibited the expression of TGF-β-stimulated PAI-1, type I collagen, and fibronectin. Clusterin inhibited TGF-β-stimulated Smad3 activity via inhibition of Smad3 phosphorylation and its nuclear translocation. Moreover, intrarenal delivery of adenovirus-expressing clusterin upregulated expression of clusterin in tubular epithelium-like cells and attenuated obstruction-induced renal fibrosis. In conclusion, clusterin attenuates renal fibrosis in obstructive nephropathy. These results suggest that upregulation of clusterin during renal injury is a protective response against the development of renal fibrosis.
簇集蛋白在几种肾脏疾病和肾毒性模型中表达上调，但上调是促进损伤还是对损伤的一种保护反应尚不清楚。在本研究中，在单侧输尿管梗阻模型中，梗阻显著增加了簇集蛋白、纤溶酶原激活物抑制剂-1（PAI-1）、I 型胶原和纤维连接蛋白的表达。与野生型小鼠相比，簇集蛋白缺陷型小鼠在梗阻时表现出更高水平的 PAI-1、I 型胶原和纤维连接蛋白，并加速了肾纤维化。在培养的大鼠肾小管上皮样细胞中，腺病毒介导的簇集蛋白过表达抑制 TGF-β刺激的 PAI-1、I 型胶原和纤维连接蛋白的表达。簇集蛋白通过抑制 Smad3 磷酸化及其核易位抑制 TGF-β刺激的 Smad3 活性。此外，腺病毒表达簇集蛋白的肾内给药上调了肾小管上皮样细胞中的簇集蛋白表达，并减轻了梗阻引起的肾纤维化。总之，簇集蛋白减轻梗阻性肾病中的肾纤维化。这些结果表明，肾损伤期间簇集蛋白的上调是对肾纤维化发展的一种保护反应。
