Tanaka Yuki, Kume Shinji, Chin-Kanasaki Masami, Araki Hisazumi, Araki Shin-Ichi, Ugi Satoshi, Sugaya Takeshi, Uzu Takashi, Maegawa Hiroshi
Department of Medicine, Shiga University of Medical Science, Tsukinokawa-Cho, Seta, Otsu, Shiga, Japan.
Department of Medicine, Shiga University of Medical Science, Tsukinokawa-Cho, Seta, Otsu, Shiga, Japan.
Biochem Biophys Res Commun. 2016 Feb 12;470(3):539-545. doi: 10.1016/j.bbrc.2016.01.109. Epub 2016 Jan 21.
Dipeptidyl peptidase (DPP)-4 inhibitors, a new class of antidiabetic agent, have recently been suggested to exert pleiotropic effects beyond glucose lowering. Renal prognosis in patients with diabetic nephropathy depends on the severity of tubulointerstitial injury induced by massive proteinuria. We thus examined the renoprotective effect of DPP-4 inhibitors on inflammation in cultured mouse proximal tubular cells stimulated with free fatty acid (FFA)-bound albumin. Linagliptin and higher concentrations of sitagliptin, vildagliptin, and alogliptin all inhibited FFA-bound albumin-induced increases in mRNA expression of MCP-1 in cultured mouse proximal tubular cells. Furthermore, linagliptin significantly inhibited tubulointerstitial injury induced by peritoneal injection of FFA-bound albumin, such as inflammation, fibrosis, and apoptosis, in mice without altering systemic characteristics including body weight, fasting blood glucose, and food intake. These results indicate that DPP-4 inhibitors pleiotropically exert a direct renoprotective effect, and may serve as an additional therapeutic strategy to protect proximal tubular cells against proteinuria in patients with diabetic nephropathy.
二肽基肽酶（DPP）-4抑制剂是一类新型抗糖尿病药物，最近有人提出其具有降血糖以外的多种效应。糖尿病肾病患者的肾脏预后取决于大量蛋白尿所致肾小管间质损伤的严重程度。因此，我们研究了DPP-4抑制剂对游离脂肪酸（FFA）结合白蛋白刺激的培养小鼠近端肾小管细胞炎症的肾脏保护作用。利格列汀以及较高浓度的西他列汀、维格列汀和阿格列汀均能抑制培养的小鼠近端肾小管细胞中FFA结合白蛋白诱导的MCP-1 mRNA表达增加。此外，利格列汀显著抑制腹腔注射FFA结合白蛋白诱导的小鼠肾小管间质损伤，如炎症、纤维化和凋亡，且不改变包括体重、空腹血糖和食物摄入量在内的全身特征。这些结果表明，DPP-4抑制剂具有多效性，可直接发挥肾脏保护作用，可能成为保护糖尿病肾病患者近端肾小管细胞免受蛋白尿影响的一种额外治疗策略。
