Reduction in chronic allograft nephropathy by inhibition of p38 mitogen-activated protein kinase.
BACKGROUND
Chronic allograft nephropathy (CAN) is the major cause for late graft loss and is therefore a key target for therapy.


METHODS
The impact of p38 mitogen-activated kinase (MAPK) on CAN was investigated by administering FR167653 (32 mg/kg/day), a specific inhibitor of p38 MAPK, for 4 weeks in addition to conventional cyclosporine therapy (1.5 mg/kg/day for 5 days) in an established experimental rat transplantation model.


RESULTS
Transplanted rats develop glomerulosclerosis, arterial obliteration, interstitial fibrosis and tubular atrophy, all of which are characteristic of CAN, resulting in shortened survival on 32 weeks. However, the inhibition of p38 MAPK by daily subcutaneous treatment with FR167653 resulted in reduced CAN with preserved renal function and prolonged survival. The FR167653-treated rats had fewer phosphorylated p38 MAPK-positive cells in treated kidneys. Concomitantly, the expression of monocyte chemoattractant protein-1/CCL2 and transforming growth factor-beta(1) was markedly reduced.


CONCLUSIONS
These results suggest that p38 MAPK phosphorylation is involved in the pathogenesis of CAN and provide evidence that p38 MAPK is a novel, appealing therapeutic target for combating CAN.
Wada
Takashi
T
Department of Gastroenterology and Nephrology, Graduate School of Medical Science, Kanazawa University, Takara-machi, Kanazawa, Japan. twada@medf.m.kanazawa-u.ac.jp
Azuma
Haruhito
H
Furuichi
Kengo
K
Sakai
Norihiko
N
Kitagawa
Kiyoki
K
Iwata
Yasunori
Y
Matsushima
Kouji
K
Takahara
Shiro
S
Yokoyama
Hitoshi
H
Kaneko
Shuichi
S
D000818:Animals; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology*; D007674:Kidney Diseases / Q000209:etiology / Q000276:immunology* / Q000517:prevention & control*; D016030:Kidney Transplantation / Q000009:adverse effects* / Q000276:immunology*; D008297:Male; D011720:Pyrazoles / Q000008:administration & dosage*; D011725:Pyridines / Q000008:administration & dosage*; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D016896:Treatment Outcome; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
C104334:FR 167653; D011720:Pyrazoles; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases