Role of FTY720 on M1 and M2 macrophages, lymphocytes, and chemokines in 5/6 nephrectomized rats.
Renal injury is accompanied by the presence of infiltrating inflammatory cells in the glomerulus and tubulointerstitium. FTY720 modifies lymphocyte migration into injured tissues by lymphocyte sequestration to secondary lymphoid organs. The purpose of this study was to examine the potential of FTY720 to influence the inflammatory response in a nonimmunological model of renal failure. Sham-operated and 5/6 nephrectomized (SNX) Sprague-Dawley rats received two different doses of FTY720 or vehicle orally for 14 wk. Treatment with FTY720 reduced glomerular and tubulointerstitial damage in SNX rats but failed to stabilize creatinine clearance. The increase in gene expression of chemokine receptors CCR1, CCR2, and CCR5 in kidneys of vehicle-treated SNX rats was significantly attenuated by high-dose FTY720. Treatment with high-dose FTY720 tended to normalize RANTES and MCP-1 renal gene expression. FTY720 affected not only glomerular and tubulointerstitial lymphocytes, but M1 and M2 phenotype macrophages were also reduced. FTY720 significantly reduced key mediators of renal inflammation and fibrosis. FTY720 also decreased immunoregulation of M2 macrophages, which are beneficial for tissue remodeling and repair.
Schaier
Matthias
M
Dept. of Nephrology, Univ. of Heidelberg, Im Neuenheimer Feld 162, 69120 Heidelberg, Germany. matthias_schaier@med.uni-heidelberg.de
Vorwalder
Stefanie
S
Sommerer
Claudia
C
Dikow
Ralf
R
Hug
Friederike
F
Gross
Marie-Luise
ML
Waldherr
Rüdiger
R
Zeier
Martin
M
D000284:Administration, Oral; D000419:Albuminuria / Q000276:immunology / Q000517:prevention & control; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D018932:Chemokine CCL2 / Q000378:metabolism; D018946:Chemokine CCL5 / Q000378:metabolism; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D003404:Creatinine / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D000068876:Fingolimod Hydrochloride; D005786:Gene Expression Regulation / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008214:Lymphocytes / Q000187:drug effects* / Q000276:immunology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D008297:Male; D009392:Nephrectomy; D009393:Nephritis / Q000276:immunology / Q000517:prevention & control; D010641:Phenotype; D011409:Propylene Glycols / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D054389:Receptors, CCR1 / Q000378:metabolism; D054390:Receptors, CCR2 / Q000378:metabolism; D019713:Receptors, CCR5 / Q000378:metabolism; D013110:Sphingosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
C491766:Ccl2 protein, rat; C515302:Ccr1 protein, rat; C515336:Ccr2 protein, rat; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D018925:Chemokines; D005353:Fibronectins; D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D011409:Propylene Glycols; D054389:Receptors, CCR1; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D053773:Transforming Growth Factor beta1; D003404:Creatinine; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine