title: Chronic tempol treatment attenuates the renal hemodynamic effects induced by a heme oxygenase inhibitor in streptozotocin diabetic rats.
abstract: Heme oxygenase-1 (HO-1) is induced by oxidative stress and plays an important role in protecting the kidney from oxidant-mediated damage in the streptozotocin (STZ) rat model of type-1 diabetes mellitus (DM-1). HO-derived metabolites, presumably carbon monoxide (CO), mediate vasodilatory influences in the renal circulation, particularly in conditions linked to elevated HO-1 protein expression or diminished nitric oxide (NO) levels. We tested the hypothesis that diabetes increases oxidative stress and induces HO-1 protein expression, which contributes to regulate renal hemodynamics in conditions of low NO bioavailability. Two weeks after the induction of diabetes with STZ (65 mg/kg iv), Sprague-Dawley rats exhibited higher renal HO-1 protein expression, hyperglycemia, and elevated renal nitrotyrosine levels than control normoglycemic animals. In anesthetized diabetic rats, renal vascular resistance (RVR) was increased, and in vivo cortical NO levels were reduced (P < 0.05) compared with control animals. Acute administration of the HO inhibitor Stannous mesoporphyrin (SnMP; 40 μmol/kg iv) did not alter renal hemodynamics in control rats, but greatly decreased glomerular filtration rate and renal blood flow, markedly increasing RVR in hyperglycemic diabetic rats. Chronic oral treatment with the SOD mimetic tempol prevented the elevation of nitrotyrosine, the HO-1 protein induction, and the increases in RVR induced by SnMP in the diabetic group, without altering basal NO concentrations or RVR. Increasing concentrations of a CO donor (CO-releasing molecule-A1) on pressurized renal interlobar arteries elicited a comparable relaxation in vessels taken from control or diabetic animals. These results suggest that oxidative stress-induced HO-1 exerts vasodilatory actions that partially maintain renal hemodynamics in uncontrolled DM-1.
authors.affiliation: Department of Physiology, Murcia School of Medicine, University of Murcia, Murcia, Spain. frodri@um.es
authors.forename: Francisca
authors.initials: F
authors.lastname: Rodriguez
authors.forename: Bernardo
authors.initials: B
authors.lastname: Lopez
authors.forename: Cayetano
authors.initials: C
authors.lastname: Perez
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Fenoy
authors.forename: Isabel
authors.initials: I
authors.lastname: Hernandez
authors.forename: David E
authors.initials: DE
authors.lastname: Stec
authors.forename: Giovanni
authors.initials: G
authors.lastname: Li Volti
authors.forename: Miguel G
authors.initials: MG
authors.lastname: Salom
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001880:Boranes / Q000494:pharmacology; D002248:Carbon Monoxide / Q000378:metabolism; D002254:Carbonates / Q000494:pharmacology; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects*; D007668:Kidney / Q000098:blood supply / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects; D013113:Spin Labels; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000975:Antioxidants; D001880:Boranes; D002254:Carbonates; D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D008665:Metalloporphyrins; D013113:Spin Labels; C503854:sodium boranocarbonate; C518404:stannous mesoporphyrin; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; C001803:tempol