FTY720 inhibits tubulointerstitial inflammation in albumin overload-induced nephropathy of rats via the Sphk1 pathway.
OBJECTIVE
FTY720, a new immunomodulatory drug with low cytotoxicity, is currently used to treat multiple sclerosis. In this study, we investigated the effects of FTY720 on inflammatory cell infiltration in albumin overload-induced nephropathy of rats.


METHODS
Male Wistar rats were subjected to right-side nephrectomy and divided into 3 groups. One week after the surgery, albumin overload (AO) group was treated with BSA (5 g·kg(-1)·d(-1), ip) for 9 weeks; AO+FTY720 group was given BSA (5 g·kg(-1)·d(-1), ip) plus FTY720 (0.5 g·kg(-1)·d(-1), ip) for 9 weeks; and control group received daily ip injection of equivalent volume of saline. All rats were killed 9 weeks after nephrectomy.


RESULTS
AO rats exhibited gradually increased urinary protein excretion accompanied by elevated urinary N-acetyl-β-O-glucosaminidase activity, and both reached their peak values at week 7. Furthermore, AO significantly increased lymphocytes and monocytes in circulation and the inflammatory cells recruited to tubulointerstitium, and the expression of inflammatory cytokines MCP-1, TNF-α and IL-6, as well as sphingosine 1-phosphate (S1P) receptors S1pr1 and S1pr3, and S1P-synthesizing enzyme sphingosine kinase 1 (Sphk1) in the kidney. Concomitant administration of FTY720 significantly attenuated all the AO-induced pathological changes.


CONCLUSIONS
FTY720 alleviates tubulointerstitium inflammation in an AO rat model of nephropathy via down-regulation of the Sphk1 pathway.
Institute of Nephrology, Division of Nephrology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China.
Min
M
Xu
Institute of Nephrology, Division of Nephrology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China.
Dan
D
Liu
Institute of Nephrology, Division of Nephrology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China.
Li-hong
LH
Ding
Institute of Nephrology, Division of Nephrology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China.
Kun-ling
KL
Ma
Institute of Nephrology, Division of Nephrology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China.
Min
M
Wu
Institute of Nephrology, Division of Nephrology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China.
Lin-li
LL
Lv
Institute of Nephrology, Division of Nephrology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China.
Yi
Y
Wen
Institute of Nephrology, Division of Nephrology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China.
Hong
H
Liu
Institute of Nephrology, Division of Nephrology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China.
Ri-ning
RN
Tang
Institute of Nephrology, Division of Nephrology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China.
Bi-cheng
BC
Liu
D000118:Acetylglucosaminidase / Q000652:urine; D000419:Albuminuria / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000652:urine; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D015536:Down-Regulation; D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D007684:Kidney Tubules / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008214:Lymphocytes / Q000187:drug effects / Q000201:enzymology; D008246:Lysophospholipids / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009395:Nephritis, Interstitial / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control* / Q000652:urine; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D011409:Propylene Glycols / Q000494:pharmacology*; D017208:Rats, Wistar; D049349:Receptors, Lysosphingolipid / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000081025:Sphingosine-1-Phosphate Receptors; D013997:Time Factors; D000099157:Sphingosine Kinase
D000118:Acetylglucosaminidase; D000893:Anti-Inflammatory Agents; D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D000081025:Sphingosine-1-Phosphate Receptors; D000099157:Sphingosine Kinase; C578616:S1PR1 protein, rat; C060506:sphingosine 1-phosphate