Hindawi Publishing Corporation International Journal of Nephrology Volume 2012, Article ID 809456, 6 pages doi:10.1155/2012/809456 Review Article Is the Antiproteinuric Effect of Cyclosporine A Independent of Its Immunosuppressive Function in T Cells? Bin Zhang and Wei Shi Department of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, 106 Zhongshan No. 2 Road, Guangzhou 510080, China Correspondence should be addressed to Bin Zhang, zhangbinyes@yahoo.com.cn and Wei Shi, vistazhang66@yahoo.cn Received 15 February 2012; Revised 20 April 2012; Accepted 3 May 2012 Academic Editor: Claudio Bazzi Copyright © 2012 B. Zhang and W. Shi. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The antiproteinuric eﬀect of cyclosporine A(CsA) has been believed to result from its immunosuppressive eﬀect on the transcription factor NFAT in T cells. However, current evidences supporting this hypothesis are missing. A recent study showed that CsA has a direct antiproteinuric eﬀect on podocytes, suggesting a novel non-immunosuppressive mechanism for CsA’s antiproteinuric eﬀect. Conditional NFATc1 activation in podoyctes per se is suﬃcient to induce proteinuria in mice, indicating that NFAT activation in podocytes is a critical pathogenic molecular event leading to podocyte injury and proteinuria. Meanwhile, evidence showed that TRPC6-mediated Ca2+ inﬂux stimulates NFAT-dependent TRPC6 expression. Altogether, these advances in podocyte research indicate that calcineurin-NFAT signal or calcineurin-synaptopodin axis has a direct proteinuric eﬀect on podocytes which raises the possibility of developing speciﬁc antiproteinuric drugs that lack the unwanted eﬀects of calcineurin or NFAT inhibition. 1. Introduction Clinically, calcineurin inhibitors (e.g., cyclosporine A, CsA) have been used to reduce proteinuria in focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), and other proteinuric kidney diseases [1]. T-cell dysfunction is associated with some forms of proteinuria, including a subset of MCD in children. This concept originally stemmed from the so called “Shalhoub hypothesis” that “lipoid nephrosis” is produced by a systemic abnormality of T- cell function [2]. For decades, FSGS was thought to be an immunologic disease resulting from the noxious eﬀect of a lymphokine on the podocyte [3]. This was the primary reason for using CsA as an immunosuppressive drug, to continue to endorse this mechanism of action despite studies demonstrating that calcineurin inhibition reduced proteinuria in nonimmunologic glomerulopathies. Actually, CsA can also reduce proteinuria in human and experi- mental Alport’s syndrome, a nonimmunological disease, raising doubts of this hypothesis [4, 5]. Moreover, although CsA eﬀectively lowered the level of proteinuria in human membranous nephropathy, the study of Ambalavanan et al. showed a more numerous and lager electron-dense immune deposits than before CsA’s therapy, indicating that whilst CsA exerts an antiproteinuric eﬀect, the drug does not modify the histologic aggravation of the glomerular lesions [6]. A recent study showed that CsA has a direct antiproteinuric eﬀect on podocytes [7].CsA blocked calcineurin-mediated dephosphorylation of the actin-organizing protein synap- topodin, a podocyte foot process cytoskeletal component, facilitating its degradation by Cathespin L. Mechanistically, this study thus identiﬁed a new calcineurin signaling pathway in kidney podocytes and attributed the antiproteinuric eﬀect of CsA to its inhibition of calcineurin-mediated degradation of synaptopodin. Thus, this antiproteinuric eﬀect was shown to be independent of T cells, at least partially. Although arguing against an antiproteinuric role of CsA through the suppression of T cells, this study did not rule out the involvement of NFAT proteins downstream of calcineurin in kidney podocytes. Our results, along with those from Wang et al. [8] and Nijenhuis et al. [9], suggested that conditional NFATc1 activation in podocytes per se is suﬃcient to induce