title: FTY720 prevents progression of renal fibrosis by inhibiting renal microvasculature endothelial dysfunction in a rat model of chronic kidney disease.
abstract: Recent studies have shown that chronic endothelial dysfunction can impair multiple aspects of renal physiology and, in turn, contribute to renal fibrosis. Sphingosine 1-phosphate (S1P) has been highlighted as an endothelial barrier-stabilizing mediator. The aim of our study was to investigate the effect of FTY720, an S1P analog, on the progression of renal fibrosis by inhibiting renal microvasculature endothelial dysfunction in a rat model of chronic kidney disease. Thirty male Sprague-Dawley rats were used in this study. Seven days after surgery, we placed the animals into three groups: sham surgery; 5/6 nephrectomized (Nx) rats; and 5/6Nx + FTY720 (1 mg/kg/day). All of the animals were sacrificed 12 weeks after surgery. We obtained and analyzed blood and kidney tissue samples from all of the groups. Glomerular capillary density and peritubular capillary (PTC) density were determined by CD31 immunostaining. The expression of transforming growth factor beta 1 (TGF-β1), collagen IV, fibronectin, endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) were analyzed by immunohistochemistry, reverse transcription-polymerase chain reaction and western blotting. The 5/6Nx group exhibited increased blood urea nitrogen and serum creatinine, visible renal histological changes, pro-fibrotic molecule (TGF-β1) and production of extracellular matrix proteins such as collagen IV and fibronectin and decreased glomerular and PTC density, compared to the sham controls (P < 0.01). We observed that treatment with FTY720 reduced these abnormalities. Furthermore, the level of NO, the expression levels of eNOS and VEGF were downregulated in the kidney tissue in 5/6Nx rats, FTY720 treatment significantly attenuated this decrease. FTY720 prevents the progression of renal fibrosis by inhibiting renal microvasculature endothelial dysfunction in a rat model of chronic kidney disease.
authors.affiliation: Institute of Nephrology, Zhong Da Hospital, School of Medicine, Southeast University, Nanjing, 210009, China.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Ni
authors.forename: Junfeng
authors.initials: J
authors.lastname: Chen
authors.forename: Mingming
authors.initials: M
authors.lastname: Pan
authors.forename: Minghui
authors.initials: M
authors.lastname: Zhang
authors.forename: Jiandong
authors.initials: J
authors.lastname: Zhang
authors.forename: Pingsheng
authors.initials: P
authors.lastname: Chen
authors.forename: Bicheng
authors.initials: B
authors.lastname: Liu
mesh_terms: D000818:Animals; D024141:Collagen Type IV / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D000068876:Fingolimod Hydrochloride; D005786:Gene Expression Regulation / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D055806:Microvessels / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D011409:Propylene Glycols / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D013110:Sphingosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D024141:Collagen Type IV; D005353:Fibronectins; D011409:Propylene Glycols; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine
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