title: Deficient renal 20-HETE release in the diabetic rat is not the result of oxidative stress.
abstract: We confirmed that release of 20-hydroxyeicosatetraenoic acid (20-HETE) from the isolated perfused kidney of diabetic rats is greatly reduced compared with age-matched control rats. The present studies were undertaken to examine potential mechanisms for the deficit in renal 20-HETE in rats with streptozotocin-induced diabetes of 3-4 wk duration. A role for oxidative stress was excluded, inasmuch as treatment of diabetic rats with tempol, an SOD mimetic, for 4 wk did not affect the renal release of 20-HETE. Similarly, chronic inhibition of nitric oxide formation with nitro-l-arginine methyl ester or aldose reductase with zopolrestat failed to alter the release of 20-HETE from the diabetic rat kidney. Inasmuch as 20-HETE may be metabolized by cyclooxygenase (COX), the expression/activity of which is increased in diabetes, we included indomethacin in the perfusate of the isolated kidney to inhibit COX but found no effect on 20-HETE release. Diabetic rats were treated for 3 wk with fenofibrate to increase expression of cytochrome P-450 (CYP4A) in an attempt to find an intervention that would restore release of 20-HETE from the diabetic rat kidney. However, fenofibrate reduced 20-HETE release in diabetic and control rat kidneys but increased expression of CYP4A. Only insulin treatment of diabetic rats for 2 wk to reverse the hyperglycemia and maintain blood glucose levels at <200 mg/dl reversed the renal deficit in 20-HETE. We conclude that oxidative stress, increased aldose reductase activity, or increased COX activity does not contribute to the renal deficit of 20-HETE in diabetes, which may be directly related to insulin deficiency.
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA.
authors.forename: Yu-Jung
authors.initials: YJ
authors.lastname: Chen
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: John
authors.initials: J
authors.lastname: Quilley
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D016718:Arachidonic Acid / Q000378:metabolism; D052160:Benzothiazoles / Q000494:pharmacology; D003497:Cyclic N-Oxides / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D042926:Cytochrome P-450 CYP4A / Q000096:biosynthesis; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism*; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011345:Fenofibrate / Q000494:pharmacology; D006893:Hydroxyeicosatetraenoic Acids / Q000172:deficiency / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007213:Indomethacin / Q000494:pharmacology; D007328:Insulin / Q000172:deficiency / Q000494:pharmacology; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008833:Microcirculation / Q000187:drug effects / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010477:Perfusion; D010793:Phthalazines / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013113:Spin Labels; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D000975:Antioxidants; D052160:Benzothiazoles; D003497:Cyclic N-Oxides; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D007004:Hypoglycemic Agents; D007328:Insulin; D010793:Phthalazines; D013113:Spin Labels; C067172:zopolrestat; D016718:Arachidonic Acid; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D000449:Aldehyde Reductase; D019001:Nitric Oxide Synthase; D042926:Cytochrome P-450 CYP4A; D011451:Prostaglandin-Endoperoxide Synthases; D011345:Fenofibrate; C001803:tempol; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin