Nephrotoxicity of Calcineurin Inhibitors in kidney epithelial cells is independent of Calcineurin and NFAT signaling

BackgroundCalcineurin inhibitors (CNI) such as Cyclosporine A (CsA) and Tacrolimus (FK506) are commonly used after renal transplantation in order to suppress the immune system. In lymphoid cells, CsA acts via the Calcineurin-NFAT axis, whereas in non-lymphoid cells, such as kidney epithelial cells, CsA induces Calcineurin inhibitor toxicity (CNT). Up to date, it is unknown via which off-targets CsA induces CNT in kidney epithelial cells.MethodsIn vitro experiments using a surrogate marker to measure CNT induction as well as in vivo studies with acute CNT, were used in order to elucidate the underlying molecular mechanism.ResultsInhibition of the NFAT axis does not show any nephrotoxicity. However, inhibition of p38 and PI3K/Akt Kinases showed induction of nephrotoxicity.ConclusionsThese findings show that CsA acts NFAT independent on kidney epithelial cells. Moreover, inhibition of certain protein kinases mimic CsA activity on kidney epithelial cells indicating that p38 and PI3K/Akt kinase pathways might be involved in CNT progression on kidney epithelial cells.