Wei Xin, Ma Yabin, Li Ya, Zhang Wenzhao, Zhong Yuting, Yu Yue, Zhang Li-Chao, Wang Zhibin, Tu Ye
Department of Clinical Pharmacy, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Department of Pharmacy, Shanghai East Hospital, Tongji University, Shanghai, China.
Front Pharmacol. 2022 Apr 19;13:876469. doi: 10.3389/fphar.2022.876469. eCollection 2022.
Podocytes damage and mesangial cells expansion are two important pathological manifestations of glomerular injury in early diabetes. Telmisartan, as an angiotensin type 1 (AT) receptor inhibitor, could improve advanced glycation end (AGE) products or angiotensin Ⅱ (Ang Ⅱ)-induced podocytes injury including detachment or apoptosis. In this current paper, we first confirmed the protective effect of telmisartan on early diabetic kidney injury in type 1 diabetic rats. Telmisartan reduced the loss of podocin and inhibited the expression of α-SMA, reflecting its protective effect on podocyte injury and mesangial proliferation, respectively. More interestingly we observed an opposite effect of telmisartan on the cell viability and apoptosis of podocytes and mesangial cells in a high-glucose environment . The anti-apoptotic effect of telmisartan on podocytes might be related to its inhibition of swiprosin-1 (a protein can mediate high glucose-induced podocyte apoptosis) expression. While telmisartan induced a high expression of PPARγ in mesangial cells, and GW9662 (a PPARγ antagonist) partially inhibited telmisartan-induced apoptosis and reduced viability of mesangial cells. In addition, high glucose-induced PKCβ1/TGFβ1 expression in mesangial cells could be blocked by telmisartan. These data provide a more precise cellular mechanism for revealing the protective effect of telmisartan in diabetic kidney injury.
足细胞损伤和系膜细胞增生是早期糖尿病肾小球损伤的两个重要病理表现。替米沙坦作为一种1型血管紧张素（AT）受体抑制剂，可改善晚期糖基化终末产物（AGE）或血管紧张素Ⅱ（AngⅡ）诱导的足细胞损伤，包括足细胞脱落或凋亡。在本论文中，我们首先证实了替米沙坦对1型糖尿病大鼠早期糖尿病肾损伤具有保护作用。替米沙坦减少了足细胞裂孔蛋白的丢失，并抑制了α-平滑肌肌动蛋白（α-SMA）的表达，分别反映了其对足细胞损伤和系膜细胞增殖的保护作用。更有趣的是，我们观察到替米沙坦在高糖环境下对足细胞和系膜细胞的细胞活力及凋亡具有相反的作用。替米沙坦对足细胞的抗凋亡作用可能与其抑制swiprosin-1（一种可介导高糖诱导足细胞凋亡的蛋白）的表达有关。而替米沙坦可诱导系膜细胞中过氧化物酶体增殖物激活受体γ（PPARγ）的高表达，且GW9662（一种PPARγ拮抗剂）可部分抑制替米沙坦诱导的系膜细胞凋亡并降低其活力。此外，替米沙坦可阻断高糖诱导的系膜细胞中蛋白激酶Cβ1（PKCβ1）/转化生长因子β1（TGFβ1）的表达。这些数据为揭示替米沙坦在糖尿病肾损伤中的保护作用提供了更精确的细胞机制。
