FK506 ameliorates proteinuria and glomerular lesions induced by anti-Thy 1.1 monoclonal antibody 1-22-3.
BACKGROUND
We have previously reported that CD4 T lymphocytes and their cytokines contribute to development of Thy 1.1 glomerulonephritis (GN). FK506 is reported to suppress the production of Th1 cytokines. The aims of this study were to elucidate the role of Th1 cytokines on mesangial alteration and to examine whether FK506 is available for therapy of mesangial proliferative GN.


METHODS
The effects of daily treatments of FK506 from day -5 and from day +1 of Thy 1.1 GN induction on glomerular alterations were analyzed.


RESULTS
FK506 treatment with 1.0 and 0.3 mg/kg body weight (BW) daily from day 1 to day 4 significantly reduced the glomerular expression of mRNA for interferon-gamma (IFN-gamma; 1.0 mg/kg BW FK506, 32.4% to the placebo group, P < 0.01) and IL-2 (55.6%, P < 0.01) on day 5. FK506 treatment from day -5 of GN induction reduced proteinuria and glomerular alteration in a dose-dependent manner. Although no side effects were detected in rats with 0.3 mg/kg BW of FK506 treatment from day +1, the treatment also ameliorated proteinuria (day 14, 3.7 +/- 0.89 vs. 19.8 +/- 12.3 mg/100 g BW/day P < 0.05) and glomerular alterations [total cell number, 63.1 +/- 3.1 vs. 80.2 +/- 7.4, P < 0.01; matrix expansion, 0.90 +/- 0.30 vs. 1.34 +/- 0.27, P < 0.05; alpha-smooth muscle actin (alphaSMA) expression; 1.20 +/- 0.12 vs. 1.96 +/- 0.29, P < 0.01] on day 14.


CONCLUSIONS
Th1 cytokines may play an important role in the development of mesangial proliferative glomerulonephritis, and could be targets for therapy. FK506 might be available for clinical use.
Ikezumi
Yohei
Y
Department of Cell Biology, Institute of Nephrology, and Department of Pediatrics, Faculty of Medicine, Niigata University, Niigata, Japan.
Kanno
Katsue
K
Koike
Hiroko
H
Tomita
Masayuki
M
Uchiyama
Makoto
M
Shimizu
Fujio
F
Kawachi
Hiroshi
H
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005921:Glomerulonephritis / Q000188:drug therapy* / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011507:Proteinuria / Q000188:drug therapy* / Q000276:immunology*; D051381:Rats; D017208:Rats, Wistar; D016559:Tacrolimus / Q000008:administration & dosage / Q000627:therapeutic use*; D018417:Th1 Cells / Q000378:metabolism; D018800:Thy-1 Antigens / Q000276:immunology*; D013997:Time Factors
D000911:Antibodies, Monoclonal; D016207:Cytokines; D007166:Immunosuppressive Agents; D018800:Thy-1 Antigens; D016559:Tacrolimus