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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 * [kg.sup.-1] * [day.sup.-1]), one of which was cotreated with paricalcitol (0.3 [micro]g * [kg.sup.-l] * [day.sup.-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-1[beta], INF-[gamma]) and adhesion molecules (monocyte chemoattractant protein-1, ICAM-1, VCAM-1) induced by GM. In addition, paricalcitol effectively reversed TGF-[beta]1-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-KB 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-KB/ERK signaling pathway and preservation of tubular epithelial integrity via inhibiting EMT process. inflammation; fibrosis doi: 10.1152/ajprenal.00471.2009

We investigated whether [alpha]-lipoic acid ([alpha]-LA), an antioxidant, attenuates the ischemia-reperfusion (I/R)-induced dysregulation of these transporters. Both renal pedicles of male Sprague-Dawley rats were clamped for 40 min. [alpha]-LA (80 mg/kg) was administered intraperitoneally before and immediately after induction of ischemia. After 2 days, the expression of aquaporins (AQPs), sodium transporters, and nitric oxide synthases (NOS) was determined in the kidney by immunoblotting and immunohistochemistry. The expression of endothelin-1 (ET-1) mRNA was determined by real-time PCR. Activities of adenylyl cyclase and guanylyl cyclase were measured by stimulated generation of cAMP and cGMP, respectively. The expression of AQP1-3 as well as that of the [[alpha].sub.1]-subunit of Na-K-ATPase, type 3 Na/H exchanger, Na-K-2Cl cotransporter, and Na-Cl cotransporter was markedly decreased in response to I/R. The expression of type VI adenylyl cyclase was decreased in I/R-injured rats, which was counteracted by the treatment of [alpha]-LA. AVP-stimulated cAMP generation was blunted in I/R rats and was then ameliorated by [alpha]-LA treatment. [alpha]-LA treatment attenuated the downregulation of AQPs and sodium transporters. The expression of endothelial NOS was decreased in I/R rats, which was prevented by [alpha]-LA. The cGMP generation in response to sodium nitroprusside was blunted in I/R rats, which was also significantly prevented by [alpha]-LA. The mRNA expression of ET-1 was increased, which was recovered to the control level by [alpha]-LA treatment. In conclusion, [alpha]-LA treatment prevents I/R-induced dysregulation of AQPs and sodium transporters in the kidney, possibly through preserving normal activities of local AVP/cAMP, nitric oxide/cGMP, and ET systems. I/R injury; aquaporins; sodium transporters; nitric oxide; endothelin