The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A.
The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A.
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钙调磷酸酶抑制剂环孢素A （cyclosporine A, CsA）的免疫抑制作用源于抑制T细胞中的活化T细胞核因子（NFAT）信号传导。CsA也用于治疗蛋白尿肾病。目前，CsA的抗蛋白尿作用归因于其免疫抑制作用。本研究表明，CsA对蛋白尿的有益作用并不依赖于T细胞中的NFAT抑制，而是源于肾足细胞中肌动蛋白细胞骨架的稳定。CsA阻断钙调磷酸酶介导的synaptopodin（足细胞中Rho gtpase的调节因子）的去磷酸化，从而保持磷酸化依赖的synaptopodin - 14-3-3β相互作用。这种相互作用的保存反过来又保护synaptopodin免受组织蛋白酶l介导的降解。这些结果代表了钙调磷酸酶信号传导的新观点，并进一步阐明了蛋白尿肾病的治疗。新型钙调磷酸酶底物如synaptopodin可能为抗蛋白尿药物提供有希望的起点，以避免长期CsA治疗的严重副作用。
The immunosuppressive action of the calcineurin inhibitor cyclosporine A (CsA) stems from the inhibition of nuclear factor of activated T cells (NFAT) signaling in T cells. CsA is also used for the treatment of proteinuric kidney diseases. As it stands, the antiproteinuric effect of CsA is attributed to its immunosuppressive action. Here we show that the beneficial effect of CsA on proteinuria is not dependent on NFAT inhibition in T cells, but rather results from the stabilization of the actin cytoskeleton in kidney podocytes. CsA blocks the calcineurin-mediated dephosphorylation of synaptopodin, a regulator of Rho GTPases in podocytes, thereby preserving the phosphorylation-dependent synaptopodin–14-3-3β interaction. Preservation of this interaction, in turn, protects synaptopodin from cathepsin L–mediated degradation. These results represent a new view of calcineurin signaling and shed further light on the treatment of proteinuric kidney diseases. Novel calcineurin substrates such as synaptopodin may provide promising starting points for antiproteinuric drugs that avoid the serious side effects of long-term CsA treatment.