Tin-mediated heme oxygenase gene activation and cytochrome P450 arachidonate hydroxylase inhibition in spontaneously hypertensive rats.
The effect of SnCl2 on the transcription of the heme oxygenase gene in spontaneously hypertensive rats was examined using cDNA for the rat heme oxygenase (HO-1). An increase in renal HO-1 mRNA levels was observed in response to SnCl2 treatment. Quantitative evaluation by scanning densitometry demonstrated a maximal increase in HO-1 mRNA 24-fold over control at 8 hours after SnCl2 administration. Nuclear runoff assay using isolated renal nuclei from SnCl2-treated rats revealed an active HO-1 gene transcription. Transcription of HO-1 in rat kidney was greatly increased within 3 hours of administration of SnCl2, as evidenced by the level of [alpha 32P]UTP incorporation into nuclear RNA. As a consequence of activation of the HO-1 gene transcription, renal enzyme activity increased eightfold at 16 hours after SnCl2, and reached maximal activity of 16-fold over control at 32 hours after injection. No significant change in cytochrome P450 fatty acid omega-hydroxylase (P450 4A) mRNA was observed after SnCl2 administration. Cytochrome P450-arachidonic acid omega/omega-1 hydroxylase(s) activity (formation of 20- and 19-HETE) was significantly reduced 24 hours after SnCl2 administration and remained lower than the control level 48 and 72 hours after injection. In addition, blood pressure was reduced from 151 +/- 2.5 mm Hg to 133 +/- 2.3 mm Hg after 48 hours of SnCl2 treatment. The reduction in blood pressure preceded natriuresis. It is concluded that SnCl2 induces activation of the HO-1 gene, which is followed by elevation in enzyme activity and a decrease in cytochrome P450-arachidonic acid omega-hydroxylase activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Da Silva
J L
JL
Rockefeller University, New York, New York 10021.
Tiefenthaler
M
M
Park
E
E
Escalante
B
B
Schwartzman
M L
ML
Levere
R D
RD
Abraham
N G
NG
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D042926:Cytochrome P-450 CYP4A; D065607:Cytochrome P-450 Enzyme Inhibitors; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics* / Q000378:metabolism; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D006973:Hypertension / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000502:physiology; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D014001:Tin / Q000494:pharmacology*; D015533:Transcriptional Activation
D065607:Cytochrome P-450 Enzyme Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D014001:Tin; C055986:19-hydroxy-5,8,11,14-eicosatetraenoic acid; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; D006419:Heme Oxygenase (Decyclizing); D042926:Cytochrome P-450 CYP4A