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.]