title: Heme Oxygenase Improves Renal Function by Potentiating Podocyte-Associated Proteins in Nω-Nitro-l-Arginine-Methyl Ester (l-NAME)-Induced Hypertension.
abstract: BACKGROUND
  Although heme-oxygenase (HO) is cytoprotective, its effects on podocyte regulators like podocalyxin, podocin, CD2-associated protein (CD2AP) in renal dysfunction in N (ω)-nitro-l-arginine-methyl ester (l-NAME) hypertension are largely unclear.
  
  
  METHODS
  Hypertension was induced in normotensive Sprague Dawley rats by administering l-NAME for 4 weeks. Enzyme immunoassay, enzyme-linked immunosorbent, histology/morphology, spectrophotometry, and western immunoblotting were used. HO was enhanced with heme-arginate (HA) or inhibited with chromium mesoporphyrin (CrMP).
  
  
  RESULTS
  Treatment with heme-arginate reduced several renal histo-pathological lesions including renal arteriolar thickening, glomerular abnormalities, tubular cast, tubular atrophy/fibrosis, and mononuclear cell infiltration in l-NAME-hypertensive rats. Similarly, HA abated the elevated levels of renal extracellular matrix/profibrotic proteins like collagen and fibronectin that deplete nephrin, a fundamental transmembrane protein that forms the scaffoldings of the podocyte slit diaphragm permitting small ions to filter, but not massive excretion of proteins, hence proteinuria. Correspondingly, HA enhanced the aberrant expression of nephrin alongside other important regulators of podocyte like podocalyxin, podocin, and CD2AP, and improved renal function by reducing albuminuria/proteinuria, while increasing creatinine clearance. The renoprotection by HA were accompanied by significant reduction of inflammatory/oxidative mediators including nuclear factor-kappaB, macrophage inflammatory protein-1-alpha, macrophage chemoattractant protein-1, tumor necrosis factor-alpha, interleukin (IL)-6, IL1β, 8-isoprostane, endothelin-1, and aldosterone. These were associated with increased levels of adiponectin, HO-1, HO activity, cyclic guanosine monophosphate, and atrial natriuretic peptide (ANP), whereas the HO inhibitor, CrMP annulled the renoprotection and exacerbated renal dysfunction.
  
  
  CONCLUSIONS
  HA improves renal function by attenuating histopathological lesions, suppressing inflammatory/oxidative mediators, abating profibrotic/extracellular matrix proteins, and reducing albuminuria/proteinuria, while concomitantly potentiating the HO-adiponectin-ANP axis, enhancing nephrin, podocin, podocalyxin, CD2AP and increasing creatinine clearance. Our study underscores the benefit of potentiating the HO-adiponectin-ANP against nephropathy.
authors.affiliation: Department of Physiology, University of Saskatchewan College of Medicine, Saskatoon, SK, Canada S7N 5E5; joseph.ndisang@usask.ca.
authors.forename: Joseph Fomusi
authors.initials: JF
authors.lastname: Ndisang
authors.affiliation: Department of Pathology & Laboratory Medicine, University of Saskatchewan College of Medicine, Saskatoon, SK, Canada S7N 5E5.
authors.forename: Rajni
authors.initials: R
authors.lastname: Chibbar
mesh_terms: D000818:Animals; D001120:Arginine / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D019610:Cytoprotection; D004195:Disease Models, Animal; D004790:Enzyme Induction; D004791:Enzyme Inhibitors; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005355:Fibrosis; D006418:Heme / Q000494:pharmacology*; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008652:Mesoporphyrins / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester; D018384:Oxidative Stress / Q000187:drug effects; D050199:Podocytes / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D015415:Biomarkers; D004791:Enzyme Inhibitors; D016326:Extracellular Matrix Proteins; D018836:Inflammation Mediators; D008652:Mesoporphyrins; C427471:chromium mesoporphyrin; D006418:Heme; D001120:Arginine; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; C048849:heme arginate; D019331:NG-Nitroarginine Methyl Ester
keywords: CD2-associated protein; adiponectin; atrial natriuretic peptide; blood pressure; extracellular matrix; heme oxygenase; hypertension; inflammation; nephrin; nephropathy; oxidative stress; podocalyxin; podocin.