Wakamatsu Ayako, Fukusumi Yoshiyasu, Hasegawa Eriko, Tomita Masayuki, Watanabe Toru, Narita Ichiei, Kawachi Hiroshi
Department of Cell Biology, Institute of Nephrology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
Department of Cell Biology, Institute of Nephrology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
Physiol Rep. 2016 Mar;4(6). doi: 10.14814/phy2.12679.
Although calcineurin (CN) is distributed in many cell types and functions in regulating cell functions, the precise roles ofCNremained in each type of the cells are not well understood yet. ACNinhibitor (CNI) has been used for steroid-resistant nephrotic syndrome. ACNIis assumed to ameliorate proteinuria by preventing the overproduction of T-cell cytokines. However, recent reports suggest thatCNIhas a direct effect on podocyte. It is accepted that a slit diaphragm (SD), a unique cell-cell junction of podocytes, is a critical barrier preventing a leak of plasma protein into urine. Therefore, we hypothesized thatCNIhas an effect on theSD In this study, we analyzed the expression ofCNin physiological and in the nephrotic model caused by the antibody against nephrin, a critical component of theSD We observed thatCNis expressed at theSDin normal rat and human kidney sections and has an interaction with nephrin. The staining ofCNat theSDwas reduced in the nephrotic model, whileCNactivity in glomeruli was increased. We also observed that the treatment with tacrolimus, aCNI, in this nephrotic model suppressed the redistribution ofCN, nephrin, and otherSDcomponents and ameliorated proteinuria. These observations suggested that the redistribution and the activation ofCNmay participate in the development of theSDinjury.
尽管钙调神经磷酸酶（CN）分布于多种细胞类型中并在调节细胞功能方面发挥作用，但CN在每种细胞类型中的确切作用尚未完全明确。一种CN抑制剂（CNI）已被用于治疗激素抵抗型肾病综合征。人们认为CNI通过阻止T细胞细胞因子的过度产生来改善蛋白尿。然而，最近的报道表明CNI对足细胞有直接作用。人们公认，裂孔隔膜（SD）是足细胞独特的细胞间连接，是防止血浆蛋白漏入尿液的关键屏障。因此，我们推测CNI对SD有影响。在本研究中，我们分析了CN在生理状态下以及在由针对SD关键成分nephrin的抗体引起的肾病模型中的表达情况。我们观察到，在正常大鼠和人类肾脏切片中，CN在SD处表达，并且与nephrin相互作用。在肾病模型中，SD处CN的染色减少，而肾小球中CN的活性增加。我们还观察到，在该肾病模型中用CNI他克莫司进行治疗可抑制CN、nephrin和其他SD成分的重新分布，并改善蛋白尿。这些观察结果表明，CN的重新分布和激活可能参与了SD损伤的发生发展。
