Differential effect of cobalt protoporphyrin on distributions of heme oxygenase in renal structure and on blood pressure in SHR.
Heme oxygenase (HO) is a microsomal enzyme that oxidatively cleaves heme to form biliverdin, releasing iron and carbon monoxide (CO). Thus, HO not only controls the availability of heme for the synthesis of hemeproteins but also generates CO, which binds to the heme moiety of hemoproteins, thereby affecting their enzymatic activity. The present study was undertaken to explore changes in the relative expression of renal HO-1 and HO-2 in response to modulators and the effect on blood pressure regulation in spontaneously hypertensive rats (SHR). Immunohistochemistry confirmed a cobalt protoporphyrin (CoPP)-mediated increase in HO-1 protein. After a single injection of CoPP (5 mg/100 gram body weight) in 7-week-old SHR, blood pressure significantly decreased (p<0.01) while renal HO activity increased 6-fold over controls. CoPP pretreatment deceased the levels of the renal cytochrome P450-derived arachidonic acid metabolite, 20-HETE, a powerful vasoconstrictor, by 65% in renal tissue. Western blot analysis demonstrated that CoPP significantly increased HO-1 protein expression in the cortex and outer medulla and, to a lesser degree, in the inner medulla of the rat kidney. HO-2 was constitutively expressed in all parts of the kidney, and did not significantly change after treatment with CoPP. These results indicate that selective induction of cortical and outer medullary HO-1 is associated with a decrease in 20-HETE and blood pressure, suggesting an important role for HO-1 activity in the regulation of urine volume, electrolyte excretion and blood pressure.
Abraham
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Department of Pharmacology, New York Medical College, Valhalla, New York 10595, USA. nader_abraham@nymc.edu
Botros
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Rezzani
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Rodella
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Bianchi
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Goodman
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D000818:Animals; D001794:Blood Pressure; D015152:Blotting, Northern; D015153:Blotting, Western; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis* / Q000378:metabolism; D051547:Heme Oxygenase-1; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism* / Q000502:physiology*; D007679:Kidney Medulla / Q000378:metabolism; D008861:Microsomes / Q000378:metabolism; D020033:Protein Isoforms; D011524:Protoporphyrins / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D006893:Hydroxyeicosatetraenoic Acids; D020033:Protein Isoforms; D011524:Protoporphyrins; D014662:Vasoconstrictor Agents; C007095:cobaltiprotoporphyrin; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C105245:heme oxygenase-2