Ban Tae H, Kim Eun N, Kim Min Y, Lim Ji H, Lee Jong H, Kim Hyung D, Yoon Hye E, Park Cheol W, Choi Bum S
Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Aging Dis. 2020 May 9;11(3):588-602. doi: 10.14336/AD.2019.0620. eCollection 2020 May.
Dipeptidyl peptidase 4 (DPP-4) inhibitors exert pleiotropic effects beyond glycemic control. We investigated the renoprotective effects of DPP-4 inhibitors on aging mice mediated by the renin-angiotensin system (RAS). C57BL/6 mice were divided into three groups: the two-month-old mice (YM group), the eighteen-month-old mice (AM group) and the eighteen-month-old, linagliptin-treated mice (AM + LIN group). Renal function was improved, based on serum creatinine and cystatin-C levels (p < 0.05 compared with the AM group for both parameters). Fibrotic areas and the levels of proteins related to fibrosis improved in the AM + LIN group (p < 0.001 compared with the AM group for all parameters). In the AM + LIN group, the DPP-4-positive area and activity and expressions of DPP-4 were decreased (p < 0.05 compared with the AM group for all parameters). The levels of proteins related to the RAS, including prorenin receptor, angiotensin-converting enzyme, angiotensin II and angiotensin 1 receptor, were decreased in the AM + LIN group (p < 0.05, p < 0.01, p < 0.05, and p < 0.01 compared with the AM group, respectively). NADPH oxidase 2 and NADPH oxidase 4 levels decreased in the AM + LIN group (p < 0.001 compared with the AM group for both proteins), whereas the levels of endothelial nitric oxide synthase (eNOS) phosphorylated at serine and superoxide dismutase 1 were increased (p < 0.01 compared with the AM group for both proteins). DPP-4 inhibitors may exert renoprotective effects via prorenin receptor/angiotensin-converting enzyme/angiotensin II/angiotensin 1 receptor axis.
二肽基肽酶4（DPP - 4）抑制剂具有血糖控制以外的多种效应。我们研究了DPP - 4抑制剂对由肾素 - 血管紧张素系统（RAS）介导的衰老小鼠的肾脏保护作用。将C57BL / 6小鼠分为三组：两个月大的小鼠（青年组）、十八个月大的小鼠（老年组）和十八个月大且接受利那格列汀治疗的小鼠（老年 + 利那格列汀组）。基于血清肌酐和胱抑素 - C水平，肾功能得到改善（两个参数与老年组相比均p < 0.05）。老年 + 利那格列汀组的纤维化面积以及与纤维化相关的蛋白质水平均有所改善（所有参数与老年组相比均p < 0.001）。在老年 + 利那格列汀组中，DPP - 4阳性面积、活性及DPP - 4的表达均降低（所有参数与老年组相比均p < 0.05）。老年 + 利那格列汀组中与RAS相关的蛋白质水平降低，包括前肾素受体、血管紧张素转换酶、血管紧张素II和血管紧张素1受体（分别与老年组相比p < 0.05、p < 0.01、p < 0.05和p < 0.01）。老年 + 利那格列汀组中NADPH氧化酶2和NADPH氧化酶4水平降低（两种蛋白质与老年组相比均p < 0.001），而丝氨酸磷酸化的内皮型一氧化氮合酶（eNOS）和超氧化物歧化酶1水平升高（两种蛋白质与老年组相比均p < 0.01）。DPP - 4抑制剂可能通过前肾素受体/血管紧张素转换酶/血管紧张素II/血管紧张素1受体轴发挥肾脏保护作用。
