Protective effect of 20-HETE analogues in experimental renal ischemia reperfusion injury

• Published in: Kidney international Vol. 75; no. 5; pp. 511 - 517
• Main Authors: Regner, Kevin R., Zuk, Anna, Van Why, Scott K., Shames, Brian D., Ryan, Robert P., Falck, John R., Manthati, Vijay L., McMullen, Meghan E., Ledbetter, Steven R., Roman, Richard J.
• Format: Journal Article
• Language: English
• Published: Basingstoke Elsevier Inc 01.03.2009; Nature Publishing Group; Elsevier Limited
• Subjects: 20-HETE; acute kidney injury; acute renal failure; Animals; Biological and medical sciences; HET0016; Hydroxyeicosatetraenoic Acids - chemistry; Hydroxyeicosatetraenoic Acids - pharmacology; ischemia-reperfusion; Kidney Diseases - drug therapy; Kidney Medulla - blood supply; Kidney Tubules - metabolism; Kidneys; Medical sciences; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Protective Agents; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Renovascular diseases; Reperfusion Injury - drug therapy; Sodium - metabolism; Urinary system involvement in other diseases. Miscellaneous; 20-HETE; HET0016; acute kidney injury; acute renal failure; ischemia-reperfusion; Kidney disease; Nephrology; Urinary system disease; Ischemia reperfusion; Acute kidney injury; Protective factor; Cardiovascular disease; Experimental study; Urology; Acute renal failure; HETE; Vascular disease; Analog; Renal ischemia reperfusion injury
• ISSN: 0085-2538; 1523-1755
• DOI: 10.1038/ki.2008.600

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.