Department of Neuroscience Cell Biology and Physiology, Boonshoft School of Medicine, College of Science and Mathematics, Wright State University, Dayton, Ohio.
Am J Physiol Renal Physiol. 2021 Mar 1;320(3):F336-F341. doi: 10.1152/ajprenal.00262.2020. Epub 2020 Nov 23.
Recently, research has directed its interests into identifying molecular pathways implicated in calcineurin inhibitor (CNI)-induced renal fibrosis. An emerging body of studies investigating calcineurin (CnA) activity has identified distinct actions of two main ubiquitously expressed isoforms: CnAα and CnAβ. CNIs have the capacity to inhibit both of these CnA isoforms. In the kidney, CnAα is required for development, whereas CnAβ predominantly modulates the immune response and glomerular hypertrophic signaling powered by activation of the transcription factor, nuclear factor of activated T lymphocytes (NFAT). Interestingly, data have shown that loss of CnAα activity contributes to the expression of profibrotic proteins in the kidney. Although this finding is of great significance, follow-up studies are needed to identify how loss of the CnAα isoform causes progressive renal damage. In addition, it is also necessary to identify downstream mediators of CnAα signaling that assist in upregulation of these profibrotic proteins. The goal of this review is to provide insight into strides taken to close the gap in elucidating CnA isoform-specific mechanisms of CNI-induced renal fibrosis. It is with hope that these contributions will lead to the development of newer generation CNIs that effectively blunt the immune response while circumventing extensive renal damage noted with long-term CNI use.
最近，研究的重点转向确定钙调神经磷酸酶抑制剂（CNI）诱导的肾纤维化所涉及的分子途径。越来越多的研究钙调神经磷酸酶（CnA）活性的研究已经确定了两种主要普遍表达的同工型的不同作用：CnAα和 CnAβ。CNI 能够抑制这两种 CnA 同工型。在肾脏中，CnAα 对于发育是必需的，而 CnAβ 主要调节免疫反应和由转录因子核因子活化 T 淋巴细胞（NFAT）激活引起的肾小球肥大信号。有趣的是，数据表明 CnAα 活性的丧失导致肾脏中促纤维化蛋白的表达。尽管这一发现具有重要意义，但需要进一步的研究来确定 CnAα 同工型的丧失如何导致进行性肾损伤。此外，还需要确定 CnAα 信号的下游介质，以协助这些促纤维化蛋白的上调。本综述的目的是深入了解阐明 CNI 诱导的肾纤维化中 CnA 同工型特异性机制方面所取得的进展。希望这些贡献将导致开发新一代的 CNI，有效地抑制免疫反应，同时避免长期使用 CNI 引起的广泛肾损伤。
