Department of Rheumatology and Immunology, The Second Affiliated Hospital of Soochow University, Suzhou, China.
Department of Hematology, The Second Affiliated Hospital of Soochow University, Suzhou, China.
Ren Fail. 2022 Dec;44(1):636-647. doi: 10.1080/0886022X.2022.2058962.
Tubulo-interstitial injury is a poor prognostic factor for lupus nephritis (LN). Here, we tested whether iguratimod could inhibit tubulo-interstitial injury in LN.
MRL/lpr mice, an animal model of lupus, were treated with iguratimod or vehicle solution. Pathological changes of kidney were evaluated blindly by the same pathologist. Renal type I collagen (COL-I), IgG, E-cadherin, fibroblast-specific protein 1 (FSP-1) were detected by immunofluorescence, immunohistochemical staining or quantitative real-time PCR. After treated with transforming growth factor β1 (TGF-β1) and iguratimod, E-cadherin, fibronectin, Smad2/3, p38 MAPK, p-Smad2/3, and p-p38 MAPK, β-catenin and TGF-β type II receptor (TGFβRII) in HK2 cells were measured by western blotting, quantitative real-time PCR or immunofluorescence.
Iguratimod reduced immune deposition along the tubular basement membrane, inhibited the tubulo-interstitial infiltration of inflammatory cells, and alleviated tubular injury in MRL/lpr mice. Moreover, Iguratimod eased the tubulo-interstitial deposition of collagen fibers, which was confirmed by decreased expression of COL-I. Furthermore, iguratimod suppressed the expression of FSP-1 and increased that of E-cadherin in renal tubular epithelial cells. In HK2 cells cultured with TGF-β1, iguratimod treatment not only reversed cellular morphological changes, but also prevented E-cadherin downregulation and fibronectin upregulation. In addition, iguratimod inhibited phosphorylation of TGFβRII, Smad2/3 and p38 MAPK in HK2 cells treated with TGF-β1, and also blocked nuclear translocation of β-catenin.
Iguratimod eased tubulo-interstitial lesions in LN, especially tubulo-interstitial fibrosis, and might have potential as a drug for inhibiting the progression of tubulo-interstitial fibrosis in LN.
肾小管间质损伤是狼疮肾炎（LN）的不良预后因素。在这里，我们检测了昔来昔布是否能抑制 LN 的肾小管间质损伤。
用昔来昔布或载体溶液处理 MRL/lpr 小鼠，一种狼疮动物模型。同一位病理学家盲法评估肾脏的病理变化。通过免疫荧光、免疫组织化学染色或实时定量 PCR 检测肾脏 I 型胶原（COL-I）、IgG、E-钙黏蛋白、成纤维细胞特异性蛋白 1（FSP-1）。用转化生长因子β1（TGF-β1）和昔来昔布处理 HK2 细胞后，通过 Western blot、实时定量 PCR 或免疫荧光检测 E-钙黏蛋白、纤维连接蛋白、Smad2/3、p38 MAPK、p-Smad2/3 和 p-p38 MAPK、β-连环蛋白和 TGF-β 型 II 受体（TGFβRII）。
昔来昔布减少了沿肾小管基底膜的免疫沉积，抑制了 MRL/lpr 小鼠肾小管间质的炎症细胞浸润，并减轻了肾小管损伤。此外，昔来昔布缓解了肾小管间质胶原纤维的沉积，这一点从 COL-I 表达的减少得到了证实。此外，昔来昔布抑制了肾小管上皮细胞中 FSP-1 的表达，增加了 E-钙黏蛋白的表达。在培养有 TGF-β1 的 HK2 细胞中，昔来昔布治疗不仅逆转了细胞形态变化，而且防止了 E-钙黏蛋白下调和纤维连接蛋白上调。此外，昔来昔布抑制了 TGF-β1 处理的 HK2 细胞中 TGFβRII、Smad2/3 和 p38 MAPK 的磷酸化，还阻断了β-连环蛋白的核转位。
昔来昔布缓解了 LN 的肾小管间质病变，特别是肾小管间质纤维化，可能有潜力成为抑制 LN 肾小管间质纤维化进展的药物。
