Abstract
BackgroundPodocytes 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.MethodsWe 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.ResultsTetrandrine 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.ConclusionsTetrandrine 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.
Highlights
Podocytes have become a crucial target for interventions in proteinuric kidney diseases
Podocyte injury is typically associated with proteinuric renal diseases, including focal segmental glomerulosclerosis (FSGS), membranous nephropathy, minimal change disease, and diabetic
Previous studies have reported that overexpressing of transient receptor potential cation channel protein 6 (TRPC6) in podocytes triggers a superior increase of intracellular C a2+ influx, which is believed to be responsible for podocyte cell injury
Summary
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. Transient receptor potential cation channel protein 6 (TRPC6), a novel slit diaphragm-associated protein in podocytes, has been identified as a nonspecific. Glomerular TRPC6 expression is increased in many hereditary and acquired proteinuric diseases. Previous studies have reported that overexpressing of TRPC6 in podocytes triggers a superior increase of intracellular C a2+ influx, which is believed to be responsible for podocyte cell injury. Increased calcium load within podocytes activates downstream signaling pathways, including calpain-1, Talin-1, nephrin and calcineurin, to modulate the activity or expression of target genes [9,10,11,12]
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