Division of Nephrology and National Clinical Research Center for Geriatrics, Kidney Research Institute, West China Hospital, Sichuan University, Chengdu, 610041, China.
Acta Pharmacol Sin. 2021 Feb;42(2):252-263. doi: 10.1038/s41401-020-00520-4. Epub 2020 Sep 18.
Diabetic nephropathy (DN) is one of the most common causes of end-stage renal disease worldwide. ω3-Fatty acids (ω3FAs) were found to attenuate kidney inflammation, glomerulosclerosis, and albuminuria in experimental and clinical studies of DN. As G protein-coupled receptor 120 (GPR120) was firstly identified as the receptor of ω3FAs, we here investigated the function of GPR120 in DN. We first examined the renal biopsies of DN patients, and found that GPR120 expression was negatively correlated with the progression of DN. Immunofluorescence staining analysis revealed that GPR120 protein was mainly located in the podocytes of the glomerulus. A potent and selective GPR120 agonist TUG-891 (35 mg · kg · d, ig) was administered to db/db mice for 4 weeks. We showed that TUG-891 administration significantly improved urinary albumin excretion, protected against podocyte injury, and reduced collagen deposition in the glomerulus. In db/db mice, TUG-891 administration significantly inhibited the mRNA and protein expression of fibronectin, collagen IV, α-SMA, TGF-β1, and IL-6, and downregulated the phosphorylation of Smad3 and STAT3 to alleviate glomerulosclerosis. Similar results were observed in high-glucose-treated MPC5 podocytes in the presence of TUG-891 (10 μM). Furthermore, we showed that TUG-891 effectively upregulated GPR120 expression, and suppressed TAK1-binding protein-1 expression as well as the phosphorylation of TAK1, IKKβ, NF-κB p65, JNK, and p38 MAPK in db/db mice and high-glucose-treated MPC5 podocytes. Knockdown of GPR120 in MPC5 podocytes caused the opposite effects of TUG-891. In summary, our results highlight that activation of GPR120 in podocytes ameliorates renal inflammation and fibrosis to protect against DN.
糖尿病肾病（DN）是全球范围内终末期肾病最常见的病因之一。ω3-脂肪酸（ω3FAs）在 DN 的实验和临床研究中被发现可减轻肾脏炎症、肾小球硬化和白蛋白尿。由于 G 蛋白偶联受体 120（GPR120）首先被鉴定为 ω3FAs 的受体，我们在此研究了 GPR120 在 DN 中的功能。我们首先检查了 DN 患者的肾活检，发现 GPR120 表达与 DN 的进展呈负相关。免疫荧光染色分析显示，GPR120 蛋白主要位于肾小球的足细胞中。一种有效的、选择性的 GPR120 激动剂 TUG-891（35mg·kg·d，ig）在 db/db 小鼠中给药 4 周。结果表明，TUG-891 给药显著改善了尿白蛋白排泄，保护了足细胞免受损伤，并减少了肾小球中的胶原沉积。在 db/db 小鼠中，TUG-891 给药显著抑制了纤维连接蛋白、IV 型胶原、α-SMA、TGF-β1 和 IL-6 的 mRNA 和蛋白表达，并下调了 Smad3 和 STAT3 的磷酸化以减轻肾小球硬化。在存在 TUG-891（10μM）的情况下，在高葡萄糖处理的 MPC5 足细胞中也观察到了类似的结果。此外，我们表明 TUG-891 可有效上调 GPR120 的表达，并抑制 TAK1 结合蛋白-1 的表达以及 TAK1、IKKβ、NF-κB p65、JNK 和 p38 MAPK 的磷酸化，在 db/db 小鼠和高葡萄糖处理的 MPC5 足细胞中。在 MPC5 足细胞中敲低 GPR120 会导致 TUG-891 的相反作用。总之，我们的结果强调了足细胞中 GPR120 的激活可改善肾脏炎症和纤维化，从而预防 DN。
