Department of Nephrology (Key laboratory of Management of Kidney Disease in Zhejiang Province), Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Tiyuchang Road 453, Hangzhou, 310007, People's Republic of China.
BMC Complement Med Ther. 2021 Dec 14;21(1):296. doi: 10.1186/s12906-021-03469-x.
Podocytes have become a crucial target for interventions in proteinuric kidney diseases. Many studies have reported that overexpression of transient receptor potential cation channel protein 6 (TRPC6) in podocyte injury upregulates intracellular Ca influx and stimulates Ca-dependent protease calpain-1 signaling. The traditional Chinese drug, tetrandrine, a nonselective Ca channel blocker, has long been used to treat chronic kidney disease. This research aimed to explore the possible mechanisms underlying the anti-proteinuric properties of tetrandrine.
We investigated the involvement of tetrandrine in Ca dependent calpain-1 signaling in mouse podocytes and adriamycin-induced nephropathy rats. Cyclosporine A (CsA) and U73122 were used as positive controls. Cell viability, cytotoxicity, Ca concentration, calpain activity, and mRNA and protein expression levels of calpain-1 signaling pathways were examined. The clinical and pathological changes were measured.
Tetrandrine decreased intracellular Ca influx in cultured TRPC6-overexpressing podocytes. In both in vitro and in vivo studies, the administration of tetrandrine downregulated calpain activity and the expression of calpain-1 and restored the expression of downstream Talin-1 and nephrin. Compared to CsA, tetrandrine treatment exhibited superior inhibitory effects on calpain activity and calpain-1 expression.
Tetrandrine has therapeutic potential in podocyte damage by blocking Ca-dependent activation of the calpain-1 signaling pathway. Tetrandrine reduced proteinuria, improved renal function, and alleviate renal pathological damage.
足细胞已成为干预蛋白尿性肾脏疾病的重要靶点。许多研究报道，足细胞损伤中瞬时受体电位阳离子通道蛋白 6（TRPC6）的过表达会增加细胞内 Ca 内流，并刺激 Ca 依赖性蛋白酶钙蛋白酶-1 信号。传统中药汉防己甲素是一种非选择性 Ca 通道阻滞剂，长期以来一直用于治疗慢性肾病。本研究旨在探讨汉防己甲素抗蛋白尿特性的可能机制。
我们研究了汉防己甲素在小鼠足细胞和阿霉素诱导的肾病大鼠中依赖 Ca 的钙蛋白酶-1 信号中的作用。环孢素 A（CsA）和 U73122 用作阳性对照。检测细胞活力、细胞毒性、Ca 浓度、钙蛋白酶活性以及钙蛋白酶-1 信号通路的 mRNA 和蛋白表达水平。测量临床和病理变化。
汉防己甲素降低了培养的 TRPC6 过表达足细胞中的细胞内 Ca 内流。在体内外研究中，汉防己甲素给药下调了钙蛋白酶活性和钙蛋白酶-1 的表达，并恢复了下游的 Talin-1 和nephrin 的表达。与 CsA 相比，汉防己甲素对钙蛋白酶活性和钙蛋白酶-1 表达的抑制作用更强。
汉防己甲素通过阻断 Ca 依赖性钙蛋白酶-1 信号通路的激活，对足细胞损伤具有治疗潜力。汉防己甲素减少蛋白尿，改善肾功能，减轻肾脏病理损伤。
