title: Differential nephron HO-1 expression following glomerular epithelial cell injury.
abstract: BACKGROUND
  In proteinuria of glomerular origin there is upregulation of heme-oxygenase (HO), the rate-limiting enzyme of heme degradation, in the nephron in a segment-specific manner. To better characterize this phenomenon, we employed a model of proteinuria resulting from disruption of the glomerular capillary permeability barrier to protein by administration of the glomerular epithelial cell toxin puromycin aminonucleoside (PAN) to rats. In this model, we assessed nephron distribution of the expression of the inducible HO isoform, HO-1, and the role of free radicals in modulating HO-1 expression.
  
  
  METHODS
  Rats were injected with either vehicle (dimethyl sulfoxide) or PAN or the spin trap free radical stabilizer alpha-phenyl-N-tert butyl nitrone (PBN), or with both PAN and PBN. Ten days following the PAN injection, urine protein, creatinine, nitric oxide (NO) and malonyldialdehyde (MDA) were measured. Kidney sections and protein lysates were assessed for changes in HO-1 expression by immunohistochemistry and Western blot analysis.
  
  
  RESULTS
  In control animals (DMSO or PBN alone) there was no proteinuria and very weak or absent HO-1 staining in nephron segments. PAN treatment induced proteinuria and increased urine MDA excretion. In these animals, there was a robust HO-1 expression mainly in tubules and in glomerular parietal but not visceral epithelial cells. Unilateral ureteral obstruction to interrupt glomerular filtration in animals treated with PAN abrogated tubular HO-1 expression in the kidney ipsilateral to the obstruction. Administration of PBN to PAN-treated animals reduced proteinuria and MDA excretion while it markedly augmented tubular HO-1 expression. This augmentation was prominent in tubular cells of the inner cortex/outer medulla.
  
  
  CONCLUSIONS
  These observations indicate that upregulation of nephron HO-1 following disruption of the glomerular permeability barrier occurs at sites downstream of this barrier and is mediated by a filtered HO-1 inducer(s). Scavenging of free radicals potentiates the effect of this inducer and unmasks nephron segments most and least capable of upregulating HO-1.
authors.affiliation: Laboratory of AIDS Pathogenesis and Molecular Therapeutics, Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Philadelphia, PA 19122, USA. dattapk@temple.edu
authors.forename: Prasun K
authors.initials: PK
authors.lastname: Datta
authors.forename: Sreenivas
authors.initials: S
authors.lastname: Reddy
authors.forename: Mukut
authors.initials: M
authors.lastname: Sharma
authors.forename: Elias A
authors.initials: EA
authors.lastname: Lianos
mesh_terms: D000818:Animals; D003497:Cyclic N-Oxides; D004195:Disease Models, Animal; D016166:Free Radical Scavengers; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009399:Nephrons / Q000378:metabolism* / Q000473:pathology; D009589:Nitrogen Oxides; D010539:Permeability; D011507:Proteinuria / Q000503:physiopathology*; D011692:Puromycin Aminonucleoside; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation
chemical_list: D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D009589:Nitrogen Oxides; C029217:phenyl-N-tert-butylnitrone; D011692:Puromycin Aminonucleoside; D051547:Heme Oxygenase-1