title: Reduction in chronic allograft nephropathy by inhibition of p38 mitogen-activated protein kinase.
abstract: 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.
authors.affiliation: Department of Gastroenterology and Nephrology, Graduate School of Medical Science, Kanazawa University, Takara-machi, Kanazawa, Japan. twada@medf.m.kanazawa-u.ac.jp
authors.forename: Takashi
authors.initials: T
authors.lastname: Wada
authors.forename: Haruhito
authors.initials: H
authors.lastname: Azuma
authors.forename: Kengo
authors.initials: K
authors.lastname: Furuichi
authors.forename: Norihiko
authors.initials: N
authors.lastname: Sakai
authors.forename: Kiyoki
authors.initials: K
authors.lastname: Kitagawa
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Iwata
authors.forename: Kouji
authors.initials: K
authors.lastname: Matsushima
authors.forename: Shiro
authors.initials: S
authors.lastname: Takahara
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yokoyama
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kaneko
mesh_terms: 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*
chemical_list: C104334:FR 167653; D011720:Pyrazoles; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases