title: The genetic inactivation of inducible nitric oxide synthase (iNOS) intensifies fibrosis and oxidative stress in the penile corpora cavernosa in type 1 diabetes.
abstract: BACKGROUND
  Endogenously elicited inducible nitric oxide synthase (iNOS) induction counteracts fibrosis and oxidative stress in penile tissues in rat models of Peyronie's disease and erectile dysfunction.
  
  
  OBJECTIVE
  The current study aimed to determine whether the genetic blockade of iNOS expression in the iNOS knock out (iNOS KO) mouse intensifies fibrosis and oxidative stress in the penile corpora cavernosa, and this is exacerbated by streptozotocin (STZ)-induced diabetes and counteracted by insulin.
  
  
  METHODS
  Quantitative assessment of histological and biochemical markers in mouse corporal tissue.
  
  
  METHODS
  Male iNOS KO and wild type (WT) mice were left untreated or injected with STZ, with or without insulin treatment. At 8 weeks, glycemia, glucosuria, and proteinuria were determined, and corporal tissue sections were obtained and subjected to Masson trichrome staining for smooth muscle (SM)/collagen ratio, and immunostaining for α-smooth muscle actin (ASMA) for, SM content, proliferating cell nuclear antigen (PCNA) for cell replication, TGFβ1 as profibrotic factor, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay for apoptosis, and xanthine oxidoreductase (XOR) for oxidative stress. Collagen was estimated by the hydroxyproline reaction.
  
  
  RESULTS
  The corporal SM/collagen ratio and SM content were reduced, and collagen content increased in iNOS KO mice as compared with WT mice, but apoptosis was decreased and cell replication increased, whereas TGFβ1 and XOR did not vary. Severe hyperglycemia caused in the WT a reduction of the corporal SM/collagen ratio and SM content and an increase in apoptosis without changes in PCNA, TGFβ1, or XOR. In the iNOS KO mouse the hyperglycemia-induced alterations were exacerbated, with additional increases in oxidative stress and TGFβ1. Insulin normalized glycemia and partially protected the SM in both the WT and the iNOS KO mice.
  
  
  CONCLUSIONS
  The antifibrotic, antioxidative, and SM-protective roles of iNOS in the penile corpora cavernosa were confirmed in the iNOS KO/STZ mouse model. These findings support the importance of endogenously-elicited iNOS induction in protecting the penile corpora cavernosa from the pro-fibrotic effects of hyperglycemia.
authors.affiliation: Charles Drew University (CDU), Department of Internal Medicine, Los Angeles, CA, USA.
authors.forename: Monica G
authors.initials: MG
authors.lastname: Ferrini
authors.forename: Steve
authors.initials: S
authors.lastname: Rivera
authors.forename: Joanne
authors.initials: J
authors.lastname: Moon
authors.forename: Dolores
authors.initials: D
authors.lastname: Vernet
authors.forename: Jacob
authors.initials: J
authors.lastname: Rajfer
authors.forename: Nestor F
authors.initials: NF
authors.lastname: Gonzalez-Cadavid
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental; D005355:Fibrosis; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007328:Insulin / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D010413:Penis / Q000378:metabolism / Q000473:pathology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014968:Xanthine Dehydrogenase / Q000378:metabolism
chemical_list: D000199:Actins; D007004:Hypoglycemic Agents; D007328:Insulin; D053773:Transforming Growth Factor beta1; D003094:Collagen; D019001:Nitric Oxide Synthase; D014968:Xanthine Dehydrogenase