Higashijima Yoshiki, Tanaka Tetsuhiro, Yamaguchi Junna, Tanaka Shinji, Nangaku Masaomi
Division of Nephrology and Endocrinology, The University of Tokyo School of Medicine, Tokyo, Japan.
Division of Nephrology and Endocrinology, The University of Tokyo School of Medicine, Tokyo, Japan
Am J Physiol Renal Physiol. 2015 Apr 15;308(8):F878-87. doi: 10.1152/ajprenal.00590.2014. Epub 2015 Feb 4.
Dipeptidyl peptidase (DPP)-4 is an enzyme that cleaves and inactivates incretin hormones capable of stimulating insulin secretion from pancreatic β-cells. DPP-4 inhibitors are now widely used for the treatment of type 2 diabetes. Experimental studies have suggested a renoprotective role of DPP-4 inhibitors in various models of diabetic kidney disease, which may be independent of lowering blood glucose levels. In the present study, we examined the effect of DPP-4 inhibitors in the rat Thy-1 glomerulonephritis model, a nondiabetic glomerular injury model. Rats were injected with OX-7 (1.2 mg/kg iv) and treated with the DPP-4 inhibitor alogliptin (20 mg·kg(-1)·day(-1)) or vehicle for 7 days orally by gavage. Alogliptin significantly reduced the number of CD68-positive inflammatory macrophages in the kidney, which was associated with a nonsignificant tendency to ameliorate glomerular injury and reduce proteinuria. Another DPP-4 inhibitor, anagliptin (300 mg·kg(-1)·day(-1) mixed with food) and a glucagon-like peptide-1 receptor agonist, exendin-4 (10 mg/kg sc), similarly reduced CD68-positive macrophage infiltration to the kidney. Furthermore, ex vivo transmigration assays using peritoneal macrophages revealed that exendin-4, but not alogliptin, dose dependently reduced monocyte chemotactic protein-1-stimulated macrophage infiltration. These data suggest that DPP-4 inhibitors reduced macrophage infiltration directly via glucagon-like peptide-1-dependent signaling in the rat Thy-1 nephritis model and indicate that the control of inflammation by DPP-4 inhibitors is useful for the treatment of nondiabetic kidney disease models.
二肽基肽酶（DPP）-4是一种能够切割并使肠促胰岛素失活的酶，这些肠促胰岛素能够刺激胰腺β细胞分泌胰岛素。DPP-4抑制剂目前广泛用于2型糖尿病的治疗。实验研究表明，DPP-4抑制剂在各种糖尿病肾病模型中具有肾脏保护作用，这可能与降低血糖水平无关。在本研究中，我们研究了DPP-4抑制剂在大鼠Thy-1肾小球肾炎模型（一种非糖尿病性肾小球损伤模型）中的作用。给大鼠注射OX-7（1.2 mg/kg静脉注射），并通过灌胃口服给予DPP-4抑制剂阿格列汀（20 mg·kg⁻¹·天⁻¹）或赋形剂，持续7天。阿格列汀显著减少了肾脏中CD68阳性炎性巨噬细胞的数量，这与改善肾小球损伤和减少蛋白尿的不显著趋势相关。另一种DPP-4抑制剂阿那格列汀（300 mg·kg⁻¹·天⁻¹与食物混合）和胰高血糖素样肽-1受体激动剂艾塞那肽-4（10 mg/kg皮下注射）同样减少了CD68阳性巨噬细胞向肾脏的浸润。此外，使用腹腔巨噬细胞进行的体外迁移试验表明，艾塞那肽-4而非阿格列汀剂量依赖性地减少了单核细胞趋化蛋白-1刺激的巨噬细胞浸润。这些数据表明，在大鼠Thy-1肾炎模型中，DPP-4抑制剂通过胰高血糖素样肽-1依赖性信号通路直接减少巨噬细胞浸润，并表明DPP-4抑制剂对炎症的控制有助于治疗非糖尿病性肾病模型。
