The tyrosine kinase inhibitor tyrphostin AG126 reduces renal ischemia/reperfusion injury in the rat.
BACKGROUND
We investigate the effects of tyrphostin AG126, an inhibitor of tyrosine kinase activity, on the renal dysfunction and injury caused by ischemia/reperfusion (I/R) of the kidney.


METHODS
Tyrphostin AG126 (5 mg/kg intraperitoneally) was administered to male Wistar rats 30 minutes prior to bilateral renal ischemia for 45 minutes followed by reperfusion for up to 48 hours. Biochemical markers of renal dysfunction and injury were measured and renal sections assessed for renal injury. Expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and formation of nitrotyrosine and poly (ADP) ribose (PAR) were assessed using immunohistochemistry. Rat proximal tubular cells (PTCs) were incubated with interferon-gamma (100 IU/mL), bacterial lipopolysaccharide (10 microg/mL), and with increasing concentrations of tyrphostin AG126 (0.0001-1 mmol/L) for 24 hours. Nitric oxide production was measured in both plasma from rats subjected to I/R and in incubation medium from PTCs.


RESULTS
After 6 hours of reperfusion, tyrphostin AG126 significantly reduced the increase in serum and urinary indicators of renal dysfunction and injury caused by I/R and reduced histologic evidence of renal injury. Tyrphostin AG126 also improved renal function (after 24 and 48 hours of reperfusion) and reduced the histologic signs of renal injury (after 48 hours of reperfusion). Tyrphostin AG126 reduced the expression of iNOS and nitric oxide levels in both rat plasma and in PTC cultures, as well as expression of COX-2. Tyrphostin AG126 also reduced nitrotyrosine and PAR formation, suggesting reduction of nitrosative stress and poly (ADP-ribose) polymerase (PARP) activation, respectively.


CONCLUSIONS
Taken together, these results show that tyrphostin AG126 significantly reduces the renal dysfunction and injury caused by I/R of the kidney. We propose that inhibition of tyrosine kinase activity may be useful against renal I/R injury.
Chatterjee
Prabal K
PK
Department of Experimental Medicine, Nephrology & Critical Care, William Harvey Research Institute, Queen Mary - University of London, London, United Kingdom.
Patel
Nimesh S A
NS
Kvale
Espen O
EO
Brown
Paul A J
PA
Stewart
Keith N
KN
Britti
Domenico
D
Cuzzocrea
Salvatore
S
Mota-Filipe
Helder
H
Thiemermann
Christoph
C
D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology; D008297:Male; D009569:Nitric Oxide / Q000097:blood; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D020032:Tyrphostins; C069028:AG 127; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D011505:Protein-Tyrosine Kinases