Paricalcitol attenuates cyclosporine-induced kidney injury in rats.
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.
Department of Internal Medicine, Chonnam National University Medical School, Gwangju 501-757, Korea.
Jeong Woo
JW
Park
Eun Hui
EH
Bae
In Jin
IJ
Kim
Seong Kwon
SK
Ma
Chan
C
Choi
JongUn
J
Lee
Soo Wan
SW
Kim
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016572:Cyclosporine / Q000633:toxicity*; D004872:Ergocalciferols / Q000494:pharmacology* / Q000627:therapeutic use; D005355:Fibrosis / Q000188:drug therapy; D007249:Inflammation / Q000517:prevention & control; D007674:Kidney Diseases / Q000139:chemically induced / Q000188:drug therapy*; D020011:Protective Agents; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome
D004872:Ergocalciferols; D020011:Protective Agents; C084656:paricalcitol; D016572:Cyclosporine