4 downregulated TRPC6 expression and reduced proteinuria. Importantly, this study showed that a deleterious feed- forward mechanism, in which TRPC6-mediated Ca2+ inﬂux stimulates NFAT-dependent TRPC6 expression, is involved in angiotensin II (Ang II)-associated podocyte injury. In vitro and in vivo models, Ang II, a key contributor to the pathogenesis of glomerular disease, increases TRPC6 expression in podocytes. The regulation of TRPC6 expres- sion by AngII is dependent on TRPC6-mediated Ca2+ inﬂux and the activation of the Ca2+-dependent calcineurin/NFAT signaling. Tian et al. [61] showed that Ang II resulted in signiﬁcant reduction in the abundance of synaptopodin, and gene silencing of TRPC6 resulted in loss of synaptopodin in podocytes in contrast, gene silencing of TRPC5 did not aﬀect synaptopodin abundance. TRPC6-depleted cells treated with CsA restored synaptopodin abundance, suggest- ing an association between Ca2+ inﬂux through TRPC5 and TRPC6 channels and synaptopodin signaling in podocytes. Schlo¨ndorﬀ et al. [58] showed that that all three TRPC6 mutations (P112Q, R895C, and E897K) to enhance channel activity lead to enhanced basal NFAT-mediated transcription in cultured podocytes, which are dependent on channel activity and are dominant when mutants are coexpressed with wild-type TRPC6. Activation of NFAT by TRPC6 mutants is blocked by inhibitors of calcineurin, calmodulin- dependent kinase II, and phosphatidylinositol 3-kinase. In addition, another study showed that calcineurin induces podocyte apoptosis in a genetic model of type 1 diabetes mellitus (Akita mice). In cultured podocytes, acti- vated NFAT promotes podocyte apoptosis in a calcineurin- dependent fashion, and induction of apoptosis by either angiotensin II or endothelin-1 was blocked by a calcineurin inhibitor (FK506). This induction of apoptosis appears to require NFAT-induced gene transcription [62]. In other cell populations, NFATc1 activation leads to distinctive changes in transcription and cellular behavior [63–65]. Interestingly, Rcan1, Wnt6, and Fzd9 were shown to be upregulated in glomeruli isolated from NFATc1nuc transgenic mice, making them potentially direct targets of NFATc1[8]. The upregulation of Rcan1, a known target of NFAT [66, 67], may reﬂect a potential regulation axis of calcineurin, NFAT, and Rcan1 in podocyte. Moreover, upregulation of Wnt signaling was found to be detrimental to podocytes [68], and Wnt signaling was also shown to be upregulated in NFATc1nuc transgenic mice, indicating that the upregulation of Wnt signaling seems to be the pathogen- esis of NFAT activation-induced podocyte injury and FSGS. 4. Conclusion The antiproteinuric eﬀect of CsA is attributed to its immuno- suppressive eﬀect. However, recently published researches showed that the eﬀect of CsA on proteinuria is not dependent on NFAT inhibition in T cells, but rather results from its eﬀects on kidney podocytes, including the stabilization of synaptopodin. Moreover, in vivo evidence from NFATc1 nuc transgenic mice and Akita mice showed NFAT activation-induced podocyte apoptosis and injury, International Journal of Nephrology and NFAT-dependent TRPC6 expression, the mutations of which have been shown to be associated with proteinuria and glomerulosclerosis in human patients. In summary, recently, there is the possibility that CsA might have a coupled nonimmunological antiproteinuric eﬀect: one as demon- strated by Faul et al. on synaptopodin and the podocyte cytoskeleton, another separate one through the inhibition of NFAT as NFAT induces proteinuria and podocyte apoptosis (Figure 1). References [1] A. 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