Tetrandrine alleviates podocyte injury via calcium-dependent calpain-1 signaling blockade

Abstract

Background 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 Ca2+ influx and stimulates Ca2+-dependent protease calpain-1 signaling. The traditional Chinese drug, tetrandrine, a nonselective Ca2+ 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. Methods We investigated the involvement of tetrandrine in Ca2+ 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, Ca2+ concentration, calpain activity, and mRNA and protein expression levels of calpain-1 signaling pathways were examined. The clinical and pathological changes were measured. Results Tetrandrine decreased intracellular Ca2+ 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. Conclusions Tetrandrine has therapeutic potential in podocyte damage by blocking Ca2+-dependent activation of the calpain-1 signaling pathway. Tetrandrine reduced proteinuria, improved renal function, and alleviate renal pathological damage.

Tetrandrine Citrate Suppresses Breast Cancer via Depletion of Glutathione Peroxidase 4 and Activation of Nuclear Receptor Coactivator 4-Mediated Ferritinophagy

“…In clinics, Tet is widely applied for the therapy of lung fibrosis, rheumatoid arthritis, silicosis, and cardiovascular disease in the Chinese population ( Cheng et al, 2021 ). A previous study has also indicated that 10 μM Tet does not affect the viability of MPC5 podocytes ( Ding et al, 2021b ). In addition, preincubation with 20 μM Tet slightly reduced the viability of HaCaT human keratinocyte cells ( Lin et al, 2019 ).…”

“…Tet is characterized by anti-allergenic and anti-inflammatory properties ( Ding et al, 2021b ). The anticancer effects of TetC have been reported in previous studies ( Yu et al, 2019 ; Wang et al, 2020 ).…”

TRPC6 mediates high glucose-induced mitochondrial fission through activation of CDK5 in cultured human podocytes

“…Multiple studies have demonstrated that TRPC6-mediated Ca 2+ influx activates cytoplasmic calpain-1 in podocytes ( Verheijden et al, 2018 ; Ding et al, 2021 ). To investigate the effect of calpain-1 on TRPC6 mediating mitochondrial fission in HG-stimulated podocytes, we first measured the activity of calpain in podocytes respectively transfected with siTRPC6 and treated with 2-APB in HG conditions, and found that TRPC6 inhibition decreased the activity of calpain in HG-treated podocytes ( Figure 5A ).…”

Tetrandrine Attenuates Podocyte Injury by Inhibiting TRPC6-Mediated RhoA/ROCK1 Pathway

“…After modeling, rats in Tet-LD, Tet-MD, Tet-HD, and CsA groups were given 4 mg/kg/d Tet (Sigma-Aldrich, USA), 8 mg/kg/d Tet, 16 mg/kg/d Tet, and 30 mg/kg/d CsA (Sigma-Aldrich) by gavage, respectively. The dosages of Tet and CsA used in this study were based on our previous report [ 27 ]. Rats in the control and ADRIA groups received the same volume of distilled water.…”