Influence of nephron mass and a phosphorylated 38 mitogen-activated protein kinase inhibitor on the development of early and long-term injury after renal warm ischaemia.
BACKGROUND
Renal ischaemia is accompanied by acute and chronic complications. Tumour necrosis factor (TNF) alpha production via p38 mitogen-activated protein kinase (MAPK) is one of the pivotal mechanisms linking ischaemia to inflammation and could be a therapeutic target. FR167653 (FR), an inhibitor of p38 MAPK and TNF-alpha production, may ameliorate renal damage through its effects on TNF-alpha.


METHODS
Warm ischaemia (WI) was induced in male pigs by bilateral clamping of the renal pedicle for 60 min or unilateral renal clamping after contralateral nephrectomy. FR was administered before and during WI, and continuously for 3 h during reperfusion in pigs exposed to the same WI conditions. Experimental groups were compared with sham-operated pigs and those subjected to unilateral nephrectomy without renal ischaemia. Renal function, fibrosis and inflammation were evaluated, and expression of monocyte chemoattractant protein 1, transforming growth factor beta and TNF-alpha was determined after 12 weeks.


RESULTS
FR significantly reduced renal failure in groups subjected to unilateral nephrectomy and bilateral renal ischaemia. Proteinuria was significantly reduced, and inflammation and expression of proinjury proteins were diminished, accompanied by a reduction in renal fibrosis.


CONCLUSIONS
Control of TNF-alpha production and activity prevents renal damage after prolonged WI.
Jayle
C
C
Institut National de la Santé et de la Recherche Médical U927 and University of Poitiers, Poitiers, France.
Faure
J P
JP
Thuillier
R
R
Goujon
J M
JM
Richer
J P
JP
Hauet
T
T
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D015153:Blotting, Western; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects* / Q000293:injuries; D008297:Male; D011720:Pyrazoles / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D051437:Renal Insufficiency / Q000517:prevention & control*; D015427:Reperfusion Injury / Q000188:drug therapy*; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D052096:Warm Ischemia; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D000894:Anti-Inflammatory Agents, Non-Steroidal; C104334:FR 167653; D011720:Pyrazoles; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases