Abstract
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.
Highlights
Calcineurin inhibitors have been used to reduce proteinuria in focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), and other proteinuric kidney diseases [1]
International Journal of Nephrology proteinuria in mice. Both studies provided in vivo evidence that NFAT activation in podocytes may be a critical pathogenic molecular event leading to proteinuria or FSGS. These advances in podocyte research indicate that calcineurin-NFAT signal or calcineurin-synaptopodin axis has a direct proteinuric effect on podocytes, and these observations raise the possibility of developing specific antiproteinuric drugs that lack the unwanted effects of calcineurin or NFAT inhibition [10]
Studies in hereditary proteinuric syndromes have uncovered that mutations of podocyte proteins, including α-actinin-4 [16], CD2AP [16, 17], nephrin [18], PLCE1 [19], podocin [20], TRPC 6 [21, 22], formin protein INF2 [23], and MYO1E [24] lead to proteinuria, podocyte foot processes effacement and podocyte actin cytoskeleton disruption [14, 25]
Summary
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]. 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. These advances in podocyte research indicate that calcineurin-NFAT signal or calcineurin-synaptopodin axis has a direct proteinuric effect on podocytes, and these observations raise the possibility of developing specific antiproteinuric drugs that lack the unwanted effects of calcineurin or NFAT inhibition [10]
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