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.
Takahashi
K
K
Department of Medicine, Vanderbilt University Medical School, Nashville, TN.
Harris
R C
RC
Capdevila
J H
JH
Karara
A
A
Makita
K
K
Jacobson
H R
HR
Munger
K A
KA
Badr
K F
KF
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