Renoprotective effects of paricalcitol on gentamicin-induced kidney injury in rats.
Vitamin D is thought to exert a protective effect on renal disease progression, but the underlying molecular mechanism remains unclear. We investigated whether paricalcitol ameliorates tubular dysfunction and fibrosis in gentamicin (GM)-induced renal injury. Two groups of rats were treated with GM (100 mg x kg(-1) x day(-1)), one of which was cotreated with paricalcitol (0.3 microg x kg(-1) x day(-1)) for 14 days and the other was not. The control group was treated with vehicle only. HK-2 cells were cultured with GM in the absence or presence of paricalcitol. Paricalcitol restored impaired renal function and the downregulated renal sodium transporters and aquaporin-1 expression caused by GM. ED-1-expressing monocyte/macrophage accumulation induced by GM was attenuated by paricalcitol treatment. Paricalcitol prevented upregulated inflammatory cytokines (TNF-alpha, IL-1beta, INF-gamma) and adhesion molecules (monocyte chemoattractant protein-1, ICAM-1, VCAM-1) induced by GM. In addition, paricalcitol effectively reversed TGF-beta1-induced epithelial-to-mesenchymal transition (EMT) process and extracellular matrix accumulation in GM-induced nephropathy. Increased collagen deposition and fibrosis in GM-treated kidney were ameliorated by paricalcitol. Paricalcitol also attenuated the upregulated NF-kappaB and phosphorylated ERK1/2 expression in HK-2 cells cultured with GM. In conclusion, paricalcitol prevents GM-induced renal injury by inhibiting renal inflammation and fibrosis, the mechanism of which is the interruption of NF-kappaB/ERK signaling pathway and preservation of tubular epithelial integrity via inhibiting EMT process.
Park
Jeong Woo
JW
Department of Internal Medicine, Chonnam National Univ. Medical School, Gwangju, Korea.
Bae
Eun Hui
EH
Kim
In Jin
IJ
Ma
Seong Kwon
SK
Choi
Chan
C
Lee
JongUn
J
Kim
Soo Wan
SW
D000818:Animals; D051398:Aquaporin 1 / Q000378:metabolism; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D002352:Carrier Proteins / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D004872:Ergocalciferols / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005355:Fibrosis / Q000517:prevention & control; D005839:Gentamicins / Q000493:pharmacokinetics; D018836:Inflammation Mediators / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced* / Q000517:prevention & control*; D007684:Kidney Tubules / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000473:pathology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D009393:Nephritis / Q000139:chemically induced / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
C496022:Aqp1 protein, rat; D050071:Bone Density Conservation Agents; D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D016207:Cytokines; D004872:Ergocalciferols; D005839:Gentamicins; D018836:Inflammation Mediators; D016328:NF-kappa B; D053773:Transforming Growth Factor beta1; D051398:Aquaporin 1; C084656:paricalcitol; D012964:Sodium; D048049:Extracellular Signal-Regulated MAP Kinases