Received December 14, 2004
Accepted on January 25, 2006

BASIC SCIENCE: Pathophysiology of Renal Disease and Progression

Heme Oxygenase-2 Deficiency Contributes to Diabetes-Mediated Increase in Superoxide Anion and Renal Dysfunction

Alvin I. Goodman ^*, Praveen N. Chander , Rita Rezzani , Michal L. Schwartzman , Raymond F. Regan ^||, Luigi Rodella , Saadet Turkseven , Elias A. Lianos ^¶, Phyllis A. Dennery ^*, and Nader G. Abraham ¹

Departments of *Medicine, Pathology, and Pharmacology, New York Medical College, Valhalla, New York; Department of Biomedical Science, Division of Anatomy, University of Brescia, Brescia, Italy; ||Department of Emergency Medicine, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania; ¶Department of Medicine, Division of Nephrology Robert Wood Johnson Medical School, New Brunswick, New Jersey; and *Department of Pediatrics, University of Pennsylvania School of Medicine, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania

¹ To whom correspondence should be addressed. E-mail: nader_abraham{at}nymc.edu.

	Abstract

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.