A NOVEL IMMUNOSUPPRESSANT FTY720 AMELIORATES PROTEINURIA IN AUTOIMMUNE GLOMERULONEPHRITIS IN BROWN NORWAY RATS AND RENAL ADRENOMEDULLIN MAY BE INVOLVED

Abstract

P769 Aims: FTY720 is a synthetic compound that is chemically modified from Isaria sinclairii. It is originally developed as a new immunosuppressive agent that remarkably prolongs graft survival in organ transplantation models without causing severe adverse reaction. Induction of apoptosis in resting and activated lymphocytes is considered to be a mechanism of action. We expected this compound might provide antiproteinuric potential, as do other immunosuppressants. Adrenomedullin (AM) and its receptor system exist in kidney. 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 the Brown Norway rats. Methods: Mercuric chloride (HgCl2) (1mg/kg body weight) was inoculated subcutaneously 3 times/week for a total of 2 weeks. FTY720 (3 or 10mg/kg body weight) was inoculated subcutaneouly daily. 40 animals were randomly divided into 5 groups of 8 animals: group 1, rats received vehicle only; group 2, rats were treated with HgCl2 alone; group 3, rats were treated with HgCl2 and FTY720 (3mg/kg body weight); group 4, rats were treated with HgCl2 and FTY720 (10mg/kg body weight); and group 5, FTY720 (10mg/kg body weight) alone. On day 13 of the experimental protocol, all rats were housed overnight in metabolic cages in order to collect urine. Serum and urine samples were obtained from all animals on day 14. Animals were sacrificed on day 14 and kidneys were excised and renal injury was evaluated. Results: The proteinuria, urinary N-acetyl-β-D-glucosaminidase (NAG) excretion and serum total cholesterol levels were significantly increased and serum albumin level was reduced in rats with HgCl2-induced GN compared with controls. FTY720 reduced proteinuria (3mg/kg:-25%; 10mg/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 significantly increased in rats with GN compared with controls (Peptide Cortex: +69%; Medulla: +82%□mRNA Cortex: +25%). FTY720 also increased these levels (Peptide Cortex: +38%; Medulla: +39%□mRNA Cortex: +20%). Renal AM levels correlated with urinary NAG excretion (Cortex: R=0.49; Medulla: R=0.54) and creatinine clearance (Cortex: R=-0.40; Medulla: R=-0.61). Conclusions: 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.