Protective effect of 20-HETE analogues in experimental renal ischemia reperfusion injury.
While it is known that the arachidonic acid metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) contributes to ischemic injury in the heart and brain, its role in kidney injury is unclear. Here we determined the effects on ischemia-reperfusion injury of the 20-HETE analogues, 20-hydroxyeicosa-5(Z), 14(Z)-dienoic acid (5,14-20-HEDE), and N-[20-hydroxyeicosa-5(Z),14(Z)-dienoyl]glycine (5,14-20-HEDGE), and of the inhibitor of 20-HETE synthesis N-hydroxy-N-(4-butyl-2 methylphenyl) formamidine (HET0016). Using Sprague-Dawley rats we found that while treatment with the inhibitor exacerbated renal injury, infusion of both 5,14-20-HEDE and 5,14-20-HEDGE significantly attenuated injury when compared to vehicle or inhibitor-treated rats. Medullary blood flow, measured by laser-Doppler flowmetry, decreased to half of the baseline one hour after reperfusion in the control rats, but 5,14-20-HEDGE completely prevented this. Treatment of control animals with 5,14-20-HEDGE increased urine output and sodium excretion without altering their mean arterial pressure or glomerular filtration rate. Our results suggest that 20-HETE analogues protect the kidney from ischemia-reperfusion injury by inhibiting renal tubular sodium transport and preventing the post-ischemic fall in medullary blood flow. Analogues of 20-HETE may be useful in the treatment of acute ischemic kidney injury.
Regner
Kevin R
KR
Department of Nephrology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Zuk
Anna
A
Van Why
Scott K
SK
Shames
Brian D
BD
Ryan
Robert P
RP
Falck
John R
JR
Manthati
Vijay L
VL
McMullen
Meghan E
ME
Ledbetter
Steven R
SR
Roman
Richard J
RJ
D000818:Animals; D006893:Hydroxyeicosatetraenoic Acids / Q000737:chemistry / Q000494:pharmacology*; D007674:Kidney Diseases / Q000188:drug therapy*; D007679:Kidney Medulla / Q000098:blood supply; D007684:Kidney Tubules / Q000378:metabolism; D020011:Protective Agents; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow; D015427:Reperfusion Injury / Q000188:drug therapy*; D012964:Sodium / Q000378:metabolism
D006893:Hydroxyeicosatetraenoic Acids; D020011:Protective Agents; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D012964:Sodium