Heme oxygenase-2 deficiency contributes to diabetes-mediated increase in superoxide anion and renal dysfunction.
Heme oxygenase-1 (HO-1) and -2 play an important role in cytoprotection and are physiologic regulators of heme-dependent protein synthesis in renal tissues. The impact of HO-2 deletion comparing hyperglycemic HO-2 (+/+) mice and HO-2 knockout (-/-) mice was examined. Hyperglycemia was induced by streptozotocin (STZ) injection, and its effect on renal HO-1/HO-2 protein, HO activity, and creatinine levels were assessed. The effect of HO induction using systemic administration of the HO inducers heme or cobalt protoporphyrin and the effect of HO inhibition using systemic administration of the HO inhibitor tin mesoporphyrin also were assessed in STZ-treated mice. In STZ-treated HO-2 (-/-) mice, there was marked renal functional impairment as reflected by an increase in plasma creatinine, associated with acute tubular damage and microvascular pathology as compared with HO-2 (+/+). In these animals, HO activity was decreased with a concomitant increase in superoxide anion. Upregulation of HO-1 in HO-2 (-/-) mice by weekly administration of cobalt protoporphyrin prevented the increase in plasma creatinine levels and tubulointerstitial and microvascular pathology. Inhibition of HO activity by administration of tin mesoporphyrin accentuated superoxide production and increased creatinine levels in hyperglycemic HO-2 (-/-) mice. In conclusion, HO-2 deficiency enhanced STZ-induced renal dysfunction and morphologic injury and HO-1 upregulation in HO-2 (-/-) mouse rescue and prevented the morphologic damage. These observations indicate that HO activity is essential in preserving renal function and morphology in STZ-induced diabetic mice probably via mitigation of concomitant oxidative stress.
Goodman
Alvin I
AI
New York Medical College, Department of Pharmacology, Grassland Road, Valhalla, NY 10595, USA.
Chander
Praveen N
PN
Rezzani
Rita
R
Schwartzman
Michal L
ML
Regan
Raymond F
RF
Rodella
Luigi
L
Turkseven
Saadet
S
Lianos
Elias A
EA
Dennery
Phyllis A
PA
Abraham
Nader G
NG
D000818:Animals; D003404:Creatinine / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology*; D006419:Heme Oxygenase (Decyclizing) / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D013311:Streptozocin / Q000633:toxicity; D013481:Superoxides / Q000378:metabolism
D013481:Superoxides; D013311:Streptozocin; D003404:Creatinine; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C105245:heme oxygenase-2