Calcineurin inhibitors: a double-edged sword

Abstract

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

Keywords: calcineurin inhibitors; calcineurin isoforms; renal fibrosis.

Graphical abstract

Figure 1.

Calcineurin inhibitors (CNIs) blunt the immune response by inactivating calcineurin phosphatase activity. CNIs bind to cytosolic proteins called immunophilins (I) (step 1) enabling the CNI-I complex to bind calcineurin active site, thereby inhibiting phosphatase activity (step 2). Upon inhibition, transcription factors such as nuclear factor of activated T cells (NFAT) are unable to become activated by dephosphorylation (step 3). This prevents NFAT translocation into the nucleus to increase IL-2 transcription (step 4), thereby blunting immune activation. [Image created with BioRender.com.]

Figure 2.

Calcineurin inhibitor (CNI)-induced nephropathy may be isoform-specific. Loss of the CnAα isoform reproduces features of cyclosporine nephrotoxicity, causing histopathological changes including matrix expansion. Further studies are necessary to confirm whether CNIs specifically inhibit the CnAα isoform (step 1), altering expression of downstream mediators that promote profibrotic gene expression and secretion (steps 2–4). CNI-induced secretion of profibrotic proteins (such as TGFβ and fibronectin) activates resident fibroblasts to differentiate into contractile myofibroblasts capable of secreting additional extracellular matrix proteins that accumulate (step 5), ultimately causing renal fibrosis. [Image created with BioRender.com.]