FR167653 improves renal recovery and decreases inflammation and fibrosis after renal ischemia reperfusion injury.
OBJECTIVE
Acute tubular necrosis (ATN) secondary to induced warm ischemia (WI) results in inflammatory and delayed fibrotic processes and remains a common clinical problem with serious consequences. Because tumor necrosis factor-alpha (TNF-alpha) is a prominent proinflammatory factor implicated in the pathophysiology of acute renal ischemia reperfusion injury (IRI), we hypothesized that FR167653 (FR), a potent inhibitor of TNF-alpha and interleukin-1beta production, may reduce IRI.


METHODS
IRI was induced in male pigs by bilateral clamping of the renal pedicle for 90 minutes (WI90), or unilateral renal clamping (90 minutes) after contralateral nephrectomy (1/2Nx90), or unilateral renal clamping without contralateral nephrectomy (WIuni90). FR was administered intravenously 60 minutes before WI (1 mg/kg/h), during WI, and continuously for 3 hours (1 mg/kg/h) during reperfusion in treated groups (FRWI90, FR1/2Nx90, or FRWIuni90). Blood and urine samples were collected between day 1 and 3 months after reperfusion for assessment of renal function. Kidneys were excised and renal tissues were collected at 3 months for morphologic and inflammation evaluation and protein analysis. Experimental groups were compared with sham operated (control) and heminephrectomized (Unif) groups without renal ischemia.


RESULTS
Three WI90 animals (43%) and five 1/2Nx90 (70%) were euthanized and necropsied at day 7 because of no urine production or poor conditions. Mortality was significantly improved after FR treatment. Survival was 100% in the control, Unif, WIuni90, and FR groups. In Unif groups, FR significantly reduced renal failure and bilateral renal ischemia (P < .05). At 3 months, proteinuria was significantly reduced in FR-treated groups (P < .01). Inflammatory cells count was also dramatically diminished in FR-treated pigs (P < .01 for CD3-positive cells). The second aspect of transient ischemia is the fibrotic process determined at 3 months. FR treatment was characterized by a reduction of renal fibrosis, particularly in Unif groups. TNF-alpha protein expression was diminished in FR-treated groups.


CONCLUSIONS
This is the first evidence that FR reduced the early and long-term effect of WI in the severe ischemia model. This effect was particularly marked against fibrosis and inflammation, which would contribute to deterioration of a patient's renal function.
Cau
Jerome
J
Inserm, U927, University Poitiers, Poitiers, France.
Favreau
Frederic
F
Zhang
Keqiang
K
Febrer
Guillaume
G
de la Motte
Gilles Regnault
GR
Ricco
Jean-Baptiste
JB
Goujon
Jean-Michel
JM
Hauet
Thierry
T
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology*; D003250:Constriction; D004195:Disease Models, Animal; D005355:Fibrosis; D007249:Inflammation / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D007262:Infusions, Intravenous; D007375:Interleukin-1 / Q000097:blood; D007668:Kidney / Q000098:blood supply* / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D007677:Kidney Function Tests; D008297:Male; D009336:Necrosis; D009392:Nephrectomy; D010766:Phosphorylation; D011507:Proteinuria / Q000276:immunology / Q000517:prevention & control; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D020127:Recovery of Function; D051437:Renal Insufficiency / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D013552:Swine; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D052096:Warm Ischemia / Q000009:adverse effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; C104334:FR 167653; D007375:Interleukin-1; D011720:Pyrazoles; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases