title: Induction of heme oxygenase-1 can halt and even reverse renal tubule-interstitial fibrosis.
abstract: BACKGROUND
  The tubule-interstitial fibrosis is the hallmark of progressive renal disease and is strongly associated with inflammation of this compartment. Heme-oxygenase-1 (HO-1) is a cytoprotective molecule that has been shown to be beneficial in various models of renal injury. However, the role of HO-1 in reversing an established renal scar has not yet been addressed.
  
  
  OBJECTIVE
  We explored the ability of HO-1 to halt and reverse the establishment of fibrosis in an experimental model of chronic renal disease.
  
  
  METHODS
  Sprague-Dawley male rats were subjected to unilateral ureteral obstruction (UUO) and divided into two groups: non-treated and Hemin-treated. To study the prevention of fibrosis, animals were pre-treated with Hemin at days -2 and -1 prior to UUO. To investigate whether HO-1 could reverse established fibrosis, Hemin therapy was given at days 6 and 7 post-surgery. After 7 and/or 14 days, animals were sacrificed and blood, urine and kidney tissue samples were collected for analyses. Renal function was determined by assessing the serum creatinine, inulin clearance, proteinuria/creatininuria ratio and extent of albuminuria. Arterial blood pressure was measured and fibrosis was quantified by Picrosirius staining. Gene and protein expression of pro-inflammatory and pro-fibrotic molecules, as well as HO-1 were performed.
  
  
  RESULTS
  Pre-treatment with Hemin upregulated HO-1 expression and significantly reduced proteinuria, albuminuria, inflammation and pro-fibrotic protein and gene expressions in animals subjected to UUO. Interestingly, the delayed treatment with Hemin was also able to reduce renal dysfunction and to decrease the expression of pro-inflammatory molecules, all in association with significantly reduced levels of fibrosis-related molecules and collagen deposition. Finally, TGF-β protein production was significantly lower in Hemin-treated animals.
  
  
  CONCLUSIONS
  Treatment with Hemin was able both to prevent the progression of fibrosis and to reverse an established renal scar. Modulation of inflammation appears to be the major mechanism behind HO-1 cytoprotection.
authors.affiliation: Laboratory of Clinical and Experimental Immunology, Nephrology Division, Federal University of São Paulo (UNIFESP), São Paulo, Brazil.
authors.forename: Matheus
authors.initials: M
authors.lastname: Correa-Costa
authors.forename: Patricia
authors.initials: P
authors.lastname: Semedo
authors.forename: Ana Paula F S
authors.initials: AP
authors.lastname: Monteiro
authors.forename: Reinaldo C
authors.initials: RC
authors.lastname: Silva
authors.forename: Rafael L
authors.initials: RL
authors.lastname: Pereira
authors.forename: Giselle M
authors.initials: GM
authors.lastname: Gonçalves
authors.forename: Georgia Daniela Marcusso
authors.initials: GD
authors.lastname: Marques
authors.forename: Marcos A
authors.initials: MA
authors.lastname: Cenedeze
authors.forename: Ana C G
authors.initials: AC
authors.lastname: Faleiros
authors.forename: Alexandre C
authors.initials: AC
authors.lastname: Keller
authors.forename: Maria H M
authors.initials: MH
authors.lastname: Shimizu
authors.forename: Antônio C
authors.initials: AC
authors.lastname: Seguro
authors.forename: Marlene A
authors.initials: MA
authors.lastname: Reis
authors.forename: Alvaro
authors.initials: A
authors.lastname: Pacheco-Silva
authors.forename: Niels O S
authors.initials: NO
authors.lastname: Câmara
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005355:Fibrosis / Q000378:metabolism*; D020869:Gene Expression Profiling; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D006427:Hemin / Q000494:pharmacology*; D007150:Immunohistochemistry / Q000379:methods; D007249:Inflammation; D007674:Kidney Diseases / Q000473:pathology; D007684:Kidney Tubules / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D016212:Transforming Growth Factor beta; D006427:Hemin; D051547:Heme Oxygenase-1