Despite its benefits, the clinical use of cyclosporine A (CsA) is limited by its nephrotoxic properties. Because paricalcitol (19-nor-1,25-hydroxyvitamin D(2)) has renoprotective effects, we tested whether it can blunt renal dysfunction and fibrosis in a rat model of CsA-induced nephropathy. Treatment with CsA decreased creatinine clearance, increased monocyte/macrophage infiltration, and increased the expression of inflammatory cytokines within the kidney. Paricalcitol reduced the decline in kidney function and pro-fibrotic changes and also blunted the increased transforming growth factor (TGF)-beta1 expression and Smad signaling. Using an in vitro model, we treated HK-2 cells with CsA and found that paricalcitol attenuated the CsA-induced increases in phosphorylated extracellular signal-regulated and c-Jun N-terminal kinases, and also prevented the activation of nuclear factor-kappaB. Paricalcitol effectively prevented TGF-beta1-induced epithelial-to-mesenchymal transitions and extracellular matrix accumulation as evidenced by attenuated collagen deposition and fibrosis in CsA-treated rats. In addition, paricalcitol decreased the number of TUNEL-positive nuclei and reduced the expression of pro-apoptotic markers in CsA-treated HK-2 cells. Thus, paricalcitol appears to attenuate CsA-induced nephropathy by suppression of inflammatory, pro-fibrotic, and apoptotic factors through inhibition of the nuclear factor-kappaB, Smad, and mitogen-activated protein kinase signaling pathways.