Calcineurin inhibitors: a double-edged sword

Y 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: CnA alpha and CnA beta. CNIs have the capacity to inhibit both of these CnA isoforms. In the kidney, CnA alpha is required for development, whereas CnA beta 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 CnA alpha 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 CnA alpha isoform causes progressive renal damage. In addition, it is also necessary to identify downstream mediators of CnA alpha 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.