title: Mechanisms by which heme oxygenase rescue renal dysfunction in obesity.
abstract: Obesity and excessive inflammation/oxidative stress are pathophysiological forces associated with kidney dysfunction. Although we recently showed that heme-oxygenase (HO) improves renal functions, the mechanisms are largely unclear. Moreover, the effects of the HO-system on podocyte cytoskeletal proteins like podocin, podocalyxin, CD2-associated-protein (CD2AP) and proteins of regeneration/repair like beta-catenin, Oct3/4, WT1 and Pax2 in renal tissue from normoglycemic obese Zucker-fatty rats (ZFs) have not been reported. Treatment with hemin reduced renal histo-pathological lesions including glomerular-hypertrophy, tubular-cast, tubular-atrophy and mononuclear cell-infiltration in ZFs. These were associated with enhanced expression of beta-catenin, Oct3/4, WT1, Pax2 and nephrin, an essential transmembrane protein required for the formation of the scaffoldings of the podocyte slit-diaphragm, permitting the filtration of small ions, but not massive excretion of proteins, hence proteinuria. Besides nephrin, hemin also enhanced other important podocyte-regulators including, podocalyxin, podocin and CD2AP. Correspondingly, important markers of renal dysfunction such as albuminuria and proteinuria were reduced, while creatinine clearance increased, suggesting improved renal function in hemin-treated ZFs. The renoprotection by hemin was accompanied by the reduction of inflammatory/oxidative mediators including, macrophage-inflammatory-protein-1α, macrophage-chemoattractant-protein-1 and 8-isoprostane, whereas HO-1, HO-activity and the total-anti-oxidant-capacity increased. Contrarily, the HO-inhibitor, stannous-mesoporphyrin nullified the reno-protection by hemin. Collectively, these data suggest that hemin ameliorates nephropathy by potentiating the expression of proteins of repair/regeneration, abating oxidative/inflammatory mediators, reducing renal histo-pathological lesions, while enhancing nephrin, podocin, podocalyxin, CD2AP and creatinine clearance, with corresponding reduction of albuminuria/proteinuria suggesting improved renal function in hemin-treated ZFs. Importantly, the concomitant potentiation regeneration proteins and podocyte cytoskeletal proteins are novel mechanisms by which hemin rescue nephropathy in obesity.
authors.affiliation: Department of Physiology, University of Saskatchewan College of Medicine, 107 Wiggins Road, Saskatoon, SK, Canada S7N 5E5. Electronic address: joseph.ndisang@usask.ca.
authors.forename: Joseph Fomusi
authors.initials: JF
authors.lastname: Ndisang
authors.affiliation: Department of Physiology, University of Saskatchewan College of Medicine, 107 Wiggins Road, Saskatoon, SK, Canada S7N 5E5.
authors.forename: Shuchita
authors.initials: S
authors.lastname: Tiwari
mesh_terms: D000818:Animals; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006427:Hemin / Q000494:pharmacology; D007668:Kidney / Q000201:enzymology* / Q000473:pathology; D007674:Kidney Diseases / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control; D008297:Male; D009765:Obesity / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control; D051381:Rats; D011924:Rats, Zucker
chemical_list: D006427:Hemin; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat
keywords: CD2-associated protein; Heme oxygenase; Oct-3/4; Podocalyxin; Podocin; beta-catenin