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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Aldehyde Reductase / antagonists & inhibitors
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Aldehyde Reductase / metabolism
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Animals
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Antioxidants / pharmacology
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Arachidonic Acid / metabolism
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Benzothiazoles / pharmacology
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Cyclic N-Oxides / pharmacology
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Cyclooxygenase Inhibitors / pharmacology
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Cytochrome P-450 CYP4A / biosynthesis
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Diabetes Mellitus, Experimental / drug therapy
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Diabetes Mellitus, Experimental / metabolism*
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Enzyme Induction
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Enzyme Inhibitors / pharmacology
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Fenofibrate / pharmacology
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Hydroxyeicosatetraenoic Acids / deficiency
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Hydroxyeicosatetraenoic Acids / metabolism*
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Hypoglycemic Agents / therapeutic use
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Indomethacin / pharmacology
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Insulin / deficiency
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Insulin / pharmacology
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Kidney / blood supply
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Kidney / drug effects
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Kidney / enzymology
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Kidney / metabolism*
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Male
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Microcirculation / drug effects
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Microcirculation / metabolism
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NG-Nitroarginine Methyl Ester / pharmacology
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Nitric Oxide / metabolism
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Nitric Oxide Synthase / antagonists & inhibitors
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Nitric Oxide Synthase / metabolism
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Oxidative Stress* / drug effects
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Perfusion
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Phthalazines / pharmacology
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Prostaglandin-Endoperoxide Synthases / metabolism
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Rats
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Rats, Wistar
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Spin Labels
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Tyrosine / analogs & derivatives
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Tyrosine / metabolism
Substances
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Antioxidants
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Benzothiazoles
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Cyclic N-Oxides
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Cyclooxygenase Inhibitors
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Enzyme Inhibitors
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Hydroxyeicosatetraenoic Acids
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Hypoglycemic Agents
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Insulin
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Phthalazines
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Spin Labels
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zopolrestat
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Arachidonic Acid
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Nitric Oxide
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3-nitrotyrosine
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Tyrosine
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20-hydroxy-5,8,11,14-eicosatetraenoic acid
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Aldehyde Reductase
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Nitric Oxide Synthase
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Cytochrome P-450 CYP4A
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Prostaglandin-Endoperoxide Synthases
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Fenofibrate
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tempol
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NG-Nitroarginine Methyl Ester
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Indomethacin