Protective effects of FR167653 on chronic allograft nephropathy by inhibiting p38 MAPK in rats.
BACKGROUND
Chronic allograft nephropathy (CAN) remains a challenge for transplant clinicians. Some novel intervention strategies may shed new light on its treatment.


METHODS
An orthotopic kidney transplant model in Fisher-to-Lewis rats was used with administration of cyclosporine alone or in combination with FR167653 (30 mg/kg/d subcuntaneously) to recipients. We analyzed renal function and urinary protein excretion. Animals were sacrificed at 30 weeks posttransplantation for histological and immunohistochemical studies.


RESULTS
Renal function among vehicle-treated rats deteriorated progressively with substantial proteinuria compared with FR167653-treated rats. FR167653 administration significantly prevented the morphlogical features of CAN and prolonged rat survivals. p38 mitogen-activated protein kinase (MAPK) expression was markedly reduced by FR167653 treatment. Meanwhile, transforming growth factor-beta1 and monocyte chemotactic protein-1 expression were significantly down-regulated among FR167653-treated hosts.


CONCLUSIONS
p38 MAPK phosphorylation correlated with CAN progression and inhibition of p38 MAPK by FR167653 may provide a potent novel therapeutic target for its prevention.
Tan
H-B
HB
Second Hospital of Hebei Medical University, Department of Nephrology, Shijiazhuang, Hebei Province, PR China. huibintan@163.com
Feng
Y
Y
Liu
M
M
Wu
Y-C
YC
D000818:Animals; D002908:Chronic Disease; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016030:Kidney Transplantation / Q000276:immunology / Q000473:pathology*; D008297:Male; D011507:Proteinuria; D011720:Pyrazoles / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D014184:Transplantation, Homologous; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
C104334:FR 167653; D007166:Immunosuppressive Agents; D011720:Pyrazoles; D011725:Pyridines; D016572:Cyclosporine; D003404:Creatinine; D048051:p38 Mitogen-Activated Protein Kinases