A p38 mitogen-activated protein kinase inhibitor protects against renal damage in a non-heart-beating donor model.
Ischemia-reperfusion injury is one of the central nonimmunologic processes involved in renal allograft dysfunction. Kidneys from non-heart beating donors (NHBD) exhibit higher rates of delayed graft function (DGF) than those from other donors. Primary nonfunction and DGF are the main barriers to the use of kidneys from NHBD. Using a pig model of NHBD transplantation, we studied the effect of FR167653 (a p38 MAP kinase inhibitor) on the recovery and reparation of kidneys exposed to both warm (WI: 1 h) and cold ischemia (24 h). Our results demonstrate that the addition of FR167653 increases the kinetics of proximal tubule cell regeneration after 60 min of WI. Hypoxia-inducible factor and vascular endothelial growth factor expression was also more important in FR167653-treated kidneys compared with those in nontreated groups. Also, expression of peripheral-type benzodiazepine receptor, involved in tissue repair, was increased in the FR167653-treated groups. At 3 mo, the protective effects of FR167653 were accompanied by a reduction of long-term inflammation process and tubulointerstitial fibrosis development associated with a limitation of ischemia-induced remodeling. This study suggests that such treatment may be useful in protocols aimed at improving the quality of renal transplants from NHBD. In addition, the beneficial role of FR167653 in limiting early injury is associated with secondary reduction in development of tubular atrophy and interstitial fibrosis which are together the hallmark of failing renal transplants. The more efficient effect was observed when FR167653 was added in combination before WI, during cold storage and reperfusion.
Doucet
Carole
C
Institut National de la Santé et de la Recherche Médicale U927, Université de Poitiers, Poitiers, France.
Milin
Serge
S
Favreau
Frederic
F
Desurmont
Thibault
T
Manguy
Emilie
E
Hébrard
William
W
Yamamoto
Yuriyo
Y
Mauco
Gérard
G
Eugene
Michel
M
Papadopoulos
Vassilios
V
Hauet
Thierry
T
Goujon
Jean Michel
JM
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005355:Fibrosis / Q000517:prevention & control; D053583:Interleukin-1beta / Q000097:blood; D007674:Kidney Diseases / Q000517:prevention & control*; D016030:Kidney Transplantation; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000473:pathology; D008297:Male; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000096:biosynthesis; D015427:Reperfusion Injury / Q000503:physiopathology*; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; C104334:FR 167653; D053583:Interleukin-1beta; D011720:Pyrazoles; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D040262:Receptors, Vascular Endothelial Growth Factor; D048051:p38 Mitogen-Activated Protein Kinases