Paricalcitol Improves Hypoxia-Induced And Tgf-Beta 1-Induced Injury In Kidney Pericytes
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES(2021)
摘要
Recently, the role of kidney pericytes in kidney fibrosis has been investigated. This study aims to evaluate the effect of paricalcitol on hypoxia-induced and TGF-beta 1-induced injury in kidney pericytes. The primary cultured pericytes were pretreated with paricalcitol (20 ng/mL) for 90 min before inducing injury, and then they were exposed to TGF-beta 1 (5 ng/mL) or hypoxia (1% O-2 and 5% CO2). TGF-beta 1 increased alpha-SMA and other fibrosis markers but reduced PDGFR beta expression in pericytes, whereas paricalcitol reversed the changes. Paricalcitol inhibited the TGF-beta 1-induced cell migration of pericytes. Hypoxia increased TGF-beta 1, alpha-SMA and other fibrosis markers but reduced PDGFR beta expression in pericyte, whereas paricalcitol reversed them. Hypoxia activated the HIF-1 alpha and downstream molecules including prolyl hydroxylase 3 and glucose transporter-1, whereas paricalcitol attenuated the activation of the HIF-1 alpha-dependent molecules and TGF-beta 1/Smad signaling pathways in hypoxic pericytes. The gene silencing of HIF-1 alpha vanished the hypoxia-induced TGF-beta 1, alpha-SMA upregulation, and PDGFR beta downregulation. The effect of paricalcitol on the HIF-1 alpha-dependent changes of fibrosis markers was not significant after the gene silencing of HIF-1 alpha. In addition, hypoxia aggravated the oxidative stress in pericytes, whereas paricalcitol reversed the oxidative stress by increasing the antioxidant enzymes in an HIF-1 alpha-independent manner. In conclusion, paricalcitol improved the phenotype changes of pericyte to myofibroblast in TGF-beta 1-stimulated pericytes. In addition, paricalcitol improved the expression of fibrosis markers in hypoxia-exposed pericytes both in an HIF-1 alpha-dependent and independent manner.
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关键词
hypoxia, paricalcitol, pericyte, pericyte-to-myofibroblast transition, TGF-beta 1, vitamin D agonist
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