A novel immunosuppressant FTY720 ameliorates proteinuria and alterations of intrarenal adrenomedullin in rats with autoimmune glomerulonephritis.
FTY720 has been originally developed as a new immunosuppressive agent, which prolongs graft survival in organ transplantation. Adrenomedullin (AM) participates in the regulation of sodium homeostasis and has renoprotective effects. The possible involvement of renal AM in the pathophysiology of glomerulonephritis (GN) and the effect of FTY720 has been evaluated in rats. HgCl2 (1 mg/kg body weight) was inoculated subcutaneously 3 times/week for a total of 2 weeks. FTY720 (3 or 10 mg/kg) was inoculated subcutaneously daily. The proteinuria, urinary N-acetyl-beta-D-glucosaminidase (NAG) excretion and serum total cholesterol levels were increased and serum albumin level was reduced in rats with HgCl2-induced GN compared with controls. FTY720 reduced proteinuria (3 mg/kg: -25%; 10 mg/kg: -41%), urinary NAG excretion (-11%; -52%) and total cholesterol level (-21%; -55%) in a dose-dependent manner. Renal AM level and its mRNA expression were increased in rats with GN compared with controls (Peptide Cortex: +69%; Medulla: +82%; mRNA Cortex: +25%). Interestingly, FTY720 additionally increased these levels (Peptide Cortex: +38%; Medulla: +39%; mRNA Cortex: +20%). Renal AM levels correlated with urinary NAG excretion and creatinine clearance. These results suggest that FTY720 suppresses the renal damage in rats with GN and renal AM may participate in the pathophysiology of GN and the renoprotective effects of FTY720.
Shi
Yi
Y
Department of Urology, Osaka University School of Medicine, Japan.
Yoshihara
Fumiki
F
Nakahama
Hajime
H
Ichimaru
Naotsugu
N
Yazawa
Koji
K
Sada
Masaharu
M
Goto
Rieko
R
Kawano
Yuhei
Y
Moriyama
Toshiki
T
Takahara
Shiro
S
Okuyama
Akihiko
A
Kangawa
Kenji
K
D053607:Adrenomedullin; D000818:Animals; D001327:Autoimmune Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D001774:Blood Chemical Analysis; D000068876:Fingolimod Hydrochloride; D005921:Glomerulonephritis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology* / Q000503:physiopathology; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000627:therapeutic use*; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008297:Male; D008627:Mercuric Chloride; D010455:Peptides / Q000378:metabolism*; D011409:Propylene Glycols / Q000378:metabolism / Q000627:therapeutic use*; D011507:Proteinuria / Q000188:drug therapy*; D011863:Radioimmunoassay; D011897:Random Allocation; D051381:Rats; D013110:Sphingosine / Q000031:analogs & derivatives; D013223:Statistics as Topic; D014556:Urine / Q000737:chemistry
D007166:Immunosuppressive Agents; D010455:Peptides; D011409:Propylene Glycols; D053607:Adrenomedullin; D008627:Mercuric Chloride; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine