BMP1 inhibitor UK383,367 attenuates renal fibrosis and inflammation in CKD
BMP1 inhibitor UK383,367 attenuates renal fibrosis and inflammation in CKD
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BMP1 抑制剂 UK383,367 减轻 CKD 中的肾纤维化和炎症
DOI：
10.1152/ajprenal.00230.2019
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发表时间：
2019-12-01
影响因子：
4.2
通讯作者：
Zhang, Aihua
中科院分区：
文献类型：
--
作者：
Bai, Mi;Lei, Juan;Zhang, Aihua
肾纤维化是慢性肾脏病（CKD）的重要病理现象，导致肾功能的进行性丧失。UK 383，367是一种前胶原蛋白C蛋白酶抑制剂，已被选为皮肤抗瘢痕形成剂的候选药物，但其在肾纤维化中的作用尚不清楚。在本研究中，将UK 383，367应用于单侧输尿管梗阻（UUO）的CKD小鼠模型以及受到转化生长因子β（1）攻击的肾小管上皮细胞（小鼠近端肾小管细胞）和肾成纤维细胞（NRK-49 F细胞）细胞系。在体内，骨形态发生蛋白1（UK 383，367的靶点）在UUO小鼠肾脏和CKD患者的肾活检组织中显著增强。引人注目的是，如Masson三色染色所示，UK 383，367给药改善了肾小管间质纤维化，这与UUO小鼠肾脏中I/III型胶原蛋白、纤连蛋白和α-平滑肌肌动蛋白的表达受阻一致。同样，梗阻肾脏中增强的炎症因子也被钝化。在体外，UK 383，367预处理抑制了转化生长因子β 1处理的小鼠近端肾小管细胞和NRK-49 F细胞中I/III型胶原蛋白、纤连蛋白和α-平滑肌肌动蛋白的诱导。综上所述，这些发现表明骨形态发生蛋白1抑制剂UK 383，367可以作为一种潜在的药物，通过作用于胶原蛋白的成熟和沉积以及随后的促纤维化反应和炎症来拮抗CKD肾纤维化。
Renal fibrosis is a key pathological phenomenon of chronic kidney disease (CKD) contributing to the progressive loss of renal function. UK383,367 is a procollagen C proteinase inhibitor that has been selected as a candidate for dermal antiscarring agents, whereas its role in renal fibrosis is unclear. In the present study, UK383,367 was applied to a CKD mouse model of unilateral ureteral obstruction (UUO) and cell lines of renal tubular epithelial cells (mouse proximal tubular cells) and renal fibroblast cells (NRK-49F cells) challenged by transforming growth factor-beta(1). In vivo, bone morphogenetic protein 1, the target of UK383,367, was significantly enhanced in UUO mouse kidneys and renal biopsies from patients with CKD. Strikingly, UK383,367 administration ameliorated tubulointerstitial fibrosis as shown by Masson's trichrome staining in line with the blocked expression of collagen type I/III, fibronectin, and alpha-smooth muscle actin in the kidneys from UUO mice. Similarly, the enhanced inflammatory factors in obstructed kidneys were also blunted. In vitro, UK383,367 pretreatment inhibited the induction of collagen type I/III, fibronectin, and alpha-smooth muscle actin in both mouse proximal tubular cells and NRK-49F cells treated with transforming growth factor-beta 1. Taken together, these findings indicate that the bone morphogenetic protein 1 inhibitor UK383,367 could serve as a potential drug in antagonizing CKD renal fibrosis by acting on the maturation and deposition of collagen and the subsequent profibrotic response and inflammation.