Division of Nephrology and National Clinical Research Center for Geriatrics, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu 610041, China; GanSu Second Provincial People's Hospital, Northwest University for Nationalities, Lanzhou 730030, China.
Division of Nephrology and National Clinical Research Center for Geriatrics, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu 610041, China.
Int Immunopharmacol. 2021 Feb;91:107279. doi: 10.1016/j.intimp.2020.107279. Epub 2020 Dec 16.
Renal fibrosis is a final common manifestation of CKD resulting in progressive loss of kidney function. The activation of SMAD3 and STAT3 played central roles in the pathogenesis of renal fibrosis, which has been recognized as potential targets for antifibrotic therapy. As we known, the potential of natural products as the candidates for drug discovery has been well recognized. Here, we identified that pectolinarigenin (PEC), as a natural flavonoid and a reported STAT3 inhibitor, dose-dependently suppressed TGFβ/SMADs activity in HEK293 cells by luciferase reporter assay. In TGFβ1-stimulated NRK-49F fibroblast, PEC blocked the phosphorylation of SMAD3 and STAT3, and downregulated the major fibrotic gene and protein expression of TGFβ, α-SMA, COL-1, and FN. Notably, oral administration of PEC at a dose of 25 mg/kg/d for 7 days or 14 days effectively ameliorated kidney injury and tubulointerstitial fibrosis after unilateral ureteral obstruction (UUO) surgery in mice. Mechanically, PEC treatment inhibited the phosphorylated activation of SMAD3 and STAT3, which further reduced the protein expression of TGFβ, α-SMA, COL-1, and FN in the obstructed kidneys of UUO mice. In summary, our results suggested that pectolinarigenin alleviated tubulointerstitial fibrosis by inhibiting the activation of SMAD3 and STAT3 signaling.
肾纤维化是 CKD 的终末共同表现，导致肾功能进行性丧失。SMAD3 和 STAT3 的激活在肾纤维化的发病机制中起核心作用，这已被认为是抗纤维化治疗的潜在靶点。众所周知，天然产物作为药物发现的候选物具有很大的潜力。在这里，我们鉴定出，作为一种天然类黄酮和报道的 STAT3 抑制剂，梨果素（PEC）通过荧光素酶报告基因检测，在 HEK293 细胞中剂量依赖性地抑制 TGFβ/SMADs 活性。在 TGFβ1 刺激的 NRK-49F 成纤维细胞中，PEC 阻断 SMAD3 和 STAT3 的磷酸化，并下调 TGFβ、α-SMA、COL-1 和 FN 的主要纤维化基因和蛋白表达。值得注意的是，PEC 以 25mg/kg/d 的剂量口服给药 7 天或 14 天，可有效改善单侧输尿管梗阻（UUO）手术后小鼠的肾脏损伤和肾小管间质纤维化。在机制上，PEC 治疗抑制 SMAD3 和 STAT3 的磷酸化激活，从而进一步减少 UUO 小鼠梗阻肾脏中 TGFβ、α-SMA、COL-1 和 FN 的蛋白表达。总之，我们的结果表明，梨果素通过抑制 SMAD3 和 STAT3 信号的激活来减轻肾小管间质纤维化。
