Role of WNT10A-Expressing Kidney Fibroblasts in Acute Interstitial Nephritis

WNT signaling mediates various physiological and pathological processes. We previously showed that WNT10A is a novel angio/stromagenic factor involved in such processes as tumor growth, wound healing and tissue fibrosis. In this study, we investigated the role of WNT10A in promoting the fibrosis that is central to the pathology of acute interstitial nephritis (AIN). We initially asked whether there is an association between kidney function (estimated glomerular filtration rate; eGFR) and WNT10A expression using kidney biopsies from 20 patients with AIN. Interestingly, patients with WNT10A expression had significantly lower eGFR than WNT10A-negative patients. However, changes in kidney function were not related to the level of expression of other WNT family members. Furthermore, there was positive correlation between WNT10A and α-SMA expression. We next investigated the involvement of WNT10A in kidney fibrosis processes using COS1 cells, a kidney fibroblast cell line. WNT10A overexpression increased the level of expression of fibronectin and peroxiredoxin 5. Furthermore, WNT10A overexpression renders cells resistant to apoptosis induced by hydrogen peroxide and high glucose. Collectively, WNT10A may induce kidney fibrosis and associate with kidney dysfunction in AIN.

WNT信号通路 (WNT signaling) 介导诸多生理与病理生理过程。本团队既往研究表明，WNT10A是一类新型血管/基质生成因子，参与肿瘤生长、伤口愈合及组织纤维化等病理生理进程。本研究聚焦于WNT10A在促进纤维化中的作用，而该纤维化正是急性间质性肾炎（acute interstitial nephritis, AIN）病理改变的核心环节。我们首先利用20例AIN患者的肾活检标本，探究肾功能（估算肾小球滤过率，estimated glomerular filtration rate, eGFR）与WNT10A表达水平的相关性。结果发现，表达WNT10A的患者其eGFR水平显著低于WNT10A阴性患者。但值得注意的是，肾功能变化与其他WNT家族成员的表达水平并无关联。此外，WNT10A的表达与α平滑肌肌动蛋白（α-smooth muscle actin, α-SMA）的表达呈正相关。后续我们采用肾成纤维细胞系COS1，进一步探究WNT10A在肾纤维化进程中的参与效应。实验数据显示，WNT10A过表达可上调纤连蛋白（fibronectin）与过氧化物还原酶5（peroxiredoxin 5）的表达水平；同时，WNT10A过表达能够使细胞抵御过氧化氢与高糖诱导的细胞凋亡。综上，WNT10A可能诱导肾纤维化，并与AIN患者的肾功能障碍存在关联。