Induction of renal arachidonate cytochrome P-450 epoxygenase after uninephrectomy: counterregulation of hyperfiltration.
After unilateral nephrectomy (UNx) in the rat, cytochrome P-450 (cP-450)-linked arachidonate enzymatic activity was markedly and specifically induced in microsomal fractions from the remaining kidney. The enzymatic activity reached 200% at 1 wk and 285% at 2 wk post-UNx as compared with non-UNx controls. Mean baseline values for GFR and RPF rate in the remaining kidney 2 wk after UNx were 1.56 +/- 0.10 and 6.47 +/- 0.35 mL/min, respectively. In these rats, the administration of ketoconazole, a cP-450 inhibitor, led to 75% inhibition of renal cP-450 arachidonate metabolism and was associated with acute augmentations in both GFR and RPF to 1.82 +/- 0.18 (P < 0.05 versus baseline) and 7.54 +/- 0.37 mL/min (P < 0.05 versus baseline), respectively. Because vasoconstrictor arachidonate epoxygenase products are endogenously generated in the rat kidney, these findings suggest that the stimulation of renal cP-450-mediated oxygenation of arachidonic acid may subserve an important counterregulatory function in mitigating the renal hyperperfusion and hyperfiltration that follow reductions in renal mass.
Department of Medicine, Vanderbilt University Medical School, Nashville, TN.
K
K
Takahashi
R C
RC
Harris
J H
JH
Capdevila
A
A
Karara
K
K
Makita
H R
HR
Jacobson
K A
KA
Munger
K F
KF
Badr
D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D000090762:Cytochrome P-450 CYP2J2; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007654:Ketoconazole / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D008297:Male; D008861:Microsomes / Q000201:enzymology; D009392:Nephrectomy; D010105:Oxygenases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation / Q000187:drug effects; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
D065607:Cytochrome P-450 Enzyme Inhibitors; D016718:Arachidonic Acid; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; D000090762:Cytochrome P-450 CYP2J2; D000469:Alkaline Phosphatase; D000254:Sodium-Potassium-Exchanging ATPase; D007654:Ketoconazole