Department of Medicine, Université de Montréal, Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), 900 Saint Denis Street, Montréal, QC, Canada H2X 0A9.
Division of Nephrology, Department of Internal Medicine, Saint Louis University, 1008 Spring Ave. St Louis, MO 63110, U.S.A.
Clin Sci (Lond). 2022 May 27;136(10):715-731. doi: 10.1042/CS20220188.
Podocyte damage and loss are the early event in the development of focal segmental glomerulosclerosis (FSGS). Podocytes express angiotensin II type-2-receptor (AT2R), which may play a key role in maintaining kidney integrity and function. Here, we examined the effects of AT2R deletion and AT2R agonist compound 21 (C21) on the evolution of FSGS. FSGS was induced by adriamycin (ADR) injection in both male wild-type (WT) and AT2R knockout (KO) mice. C21 was administered to WT-FSGS mice either one day before or 7 days after ADR (Pre-C21 or Post-C21), using two doses of C21 at either 0.3 (low dose, LD) or 1.0 (high dose, HD) mg/kg/day. ADR-induced FSGS was more severe in AT2RKO mice compared with WT-FSGS mice, and included profound podocyte loss, glomerular fibrosis, and albuminuria. Glomerular cathepsin L expression increased more in AT2RKO-FSGS than in WT-FSGS mice. C21 treatment ameliorated podocyte injury, most significantly in the Pre C21-HD group, and inhibited glomerular cathepsin L expression. In vitro, Agtr2 knock-down in mouse podocyte cell line given ADR confirmed the in vivo data. Mechanistically, C21 inhibited cathepsin L expression, which protected synaptopodin from destruction and stabilized actin cytoskeleton. C21 also prevented podocyte apoptosis. In conclusion, AT2R activation by C21 ameliorated ADR-induced podocyte injury in mice by the inhibition of glomerular cathepsin L leading to the maintenance of podocyte integrity and prevention of podocyte apoptosis.
足细胞损伤和丢失是局灶节段性肾小球硬化症 (FSGS) 发展的早期事件。足细胞表达血管紧张素 II 型受体 (AT2R)，它可能在维持肾脏完整性和功能方面发挥关键作用。在这里，我们研究了 AT2R 缺失和 AT2R 激动剂化合物 21 (C21) 对 FSGS 发展的影响。FSGS 通过阿霉素 (ADR) 注射在雄性野生型 (WT) 和 AT2R 敲除 (KO) 小鼠中诱导。C21 在 ADR 前一天或 ADR 后 7 天 (Pre-C21 或 Post-C21) 给予 WT-FSGS 小鼠，使用两种剂量的 C21，剂量分别为 0.3 (低剂量，LD) 或 1.0 (高剂量，HD) mg/kg/天。与 WT-FSGS 小鼠相比，ADR 诱导的 FSGS 在 AT2RKO 小鼠中更为严重，包括严重的足细胞丢失、肾小球纤维化和白蛋白尿。肾小球组织蛋白酶 L 的表达在 AT2RKO-FSGS 小鼠中比 WT-FSGS 小鼠中增加更多。C21 治疗改善了足细胞损伤，在 Pre C21-HD 组最为明显，并抑制了肾小球组织蛋白酶 L 的表达。在体外，给予 ADR 的小鼠足细胞系中 Agtr2 敲低证实了体内数据。在机制上，C21 抑制组织蛋白酶 L 的表达，从而保护突触蛋白免受破坏并稳定肌动蛋白细胞骨架。C21 还可防止足细胞凋亡。总之，C21 通过抑制肾小球组织蛋白酶 L 来激活 AT2R，从而改善 ADR 诱导的小鼠足细胞损伤，从而维持足细胞的完整性并防止足细胞凋亡。
