title: Tin-mediated heme oxygenase gene activation and cytochrome P450 arachidonate hydroxylase inhibition in spontaneously hypertensive rats.
abstract: 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)
authors.affiliation: Rockefeller University, New York, New York 10021.
authors.forename: J L
authors.initials: JL
authors.lastname: Da Silva
authors.forename: M
authors.initials: M
authors.lastname: Tiefenthaler
authors.forename: E
authors.initials: E
authors.lastname: Park
authors.forename: B
authors.initials: B
authors.lastname: Escalante
authors.forename: M L
authors.initials: ML
authors.lastname: Schwartzman
authors.forename: R D
authors.initials: RD
authors.lastname: Levere
authors.forename: N G
authors.initials: NG
authors.lastname: Abraham
mesh_terms: 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
chemical_list: 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