title: FTY720 attenuates tubulointerstitial inflammation and fibrosis in subtotally nephrectomized rats.
abstract: Tubulointerstitial fibrosis is a common pathway that leads to kidney failure, and persistent tubulointerstitial inflammation is a key event in the development of tubulointerstitial fibrosis. The new immunosuppressive drug FTY720 modifies lymphocyte migration into injured tissues by sequestering lymphocytes within secondary lymphoid organs. However, its therapeutic effect on tubulointerstitial inflammation and fibrosis had not been well understood. This study was designed to explore the effect of FTY720 on tubulointerstitial inflammation and fibrosis in subtotally nephrectomized (SNX) rats. In total, 24 male Sprague-Dawley rats were used. Seven days after 5/6 nephrectomy, rats were randomized to FTY720 (1 mg/kg/d) and placebo-treated groups. Sham-operated rats served as controls. FTY720 significantly attenuated the rise in proteinuria, serum creatinine, urea nitrogen and N-acetyl-β-D-glucosaminidase activity in SNX rats, and reduced the count of peripheral white blood cells and lymphocytes in SNX rats. Morphological analysis revealed that there was severe tubulointerstitial inflammation and fibrosis in SNX group and much more tubulointerstitial infiltrating inflammatory cells with high expression of CD3, CD4, CD8, CD20, CD68, CD163 and CCR-7 in SNX group, as compared with the controls, but the lesions were attenuated significantly by treatment with FTY720. Furthermore, the expressions of proinflammatory molecules (IL-6, TNF-α and MCP-1), profibrotic molecule (TGF-β1) and production of extracellular matrix proteins such as fibronectin and types I and III collagens were upregulated in SNX rats. FTY720 administration significantly reduced these abnormalities. In summary, FTY720 exerts therapeutic effects on tubulointerstitial fibrosis in SNX rats by inhibiting the tubulointerstitial inflammatory response.
authors.affiliation: Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China.
authors.forename: Hai-Feng
authors.initials: HF
authors.lastname: Ni
authors.forename: Jun-Feng
authors.initials: JF
authors.lastname: Chen
authors.forename: Ming-Hui
authors.initials: MH
authors.lastname: Zhang
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Pan
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Zhang
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Ri-Ning
authors.initials: RN
authors.lastname: Tang
authors.forename: Kun-Ling
authors.initials: KL
authors.lastname: Ma
authors.forename: Bi-Cheng
authors.initials: BC
authors.lastname: Liu
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D018932:Chemokine CCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis / Q000209:etiology / Q000276:immunology / Q000473:pathology; D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D007684:Kidney Tubules / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008214:Lymphocytes / Q000187:drug effects / Q000502:physiology; D008297:Male; D009392:Nephrectomy / Q000379:methods; D009395:Nephritis, Interstitial / Q000150:complications / Q000188:drug therapy / Q000276:immunology; D011409:Propylene Glycols / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051437:Renal Insufficiency / Q000209:etiology / Q000276:immunology / Q000473:pathology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D018932:Chemokine CCL2; D007166:Immunosuppressive Agents; D015850:Interleukin-6; D011409:Propylene Glycols; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine