title: Peroxynitrite mediates glomerular lesion of diabetic rat via JAK/STAT signaling pathway.
abstract: BACKGROUND
  Peroxynitrite, a highly reactive oxidant produced by the reaction of nitric oxide with free radicals superoxide, has been indicated to be involved in many diseases. However, the contributions of peroxynitrite to diabetic nephropathy and the underlying mechanism have not been fully explored.
  
  
  OBJECTIVE
  The present study was designed to evaluate the role and the underlying mechanism of peroxynitrite in glomerular lesion of diabetic rat.
  
  
  METHODS
  Diabetes was induced in male Wistar rats by i.p. injection of streptozotocin, and urate was used as a specific scavenger of peroxynitrite; the pathological changes of rat glomerulus were evaluated by hematoxylin and eosin, periodic acid-Schiff staining and transmission electron microscopy observation; immunohistochemistry and Western blot were used to detect the content of nitrotyrosine (the marker of peroxynitrite) in renal cortex; the expression levels of tyrosine phosphorylation of JAK2, STAT1, and STAT3 were assessed by Western blot assay; RT-PCR and Western blot were used to assay expression levels of transforming growth factor (TGF)-beta1 and fibronectin; biochemical indicators of renal function were also detected.
  
  
  RESULTS
  The content of nitrotyrosine was increased, consistent with the pathological changes of glomerulus and renal dysfunction in the diabetes group. Urate prevented the formation of nitrotyrosine in rat glomerulus and attenuated the pathological alterations. Furthermore, urate inhibited the activation of JAK2, STAT1, and STAT3. Finally, homogenates from renal cortices demonstrated reduced expression of TGF- beta1 and fibronectin under urate treatment.
  
  
  CONCLUSIONS
  Our findings thus provides in vivo evidence that exaggerated peroxynitrite formation mediates the glomerular lesion in, at least, Type 1 diabetes, which may function through JAK/STAT signaling pathway.
authors.affiliation: Department of Pathology, Hebei Medical University, No. 361 East Zhongshan Road, Shijiazhuang, Hebei 050017, China.
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: H
authors.initials: H
authors.lastname: Liu
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.forename: Q
authors.initials: Q
authors.lastname: Liu
authors.forename: X M
authors.initials: XM
authors.lastname: Wang
authors.forename: Y
authors.initials: Y
authors.lastname: Shi
authors.forename: H
authors.initials: H
authors.lastname: Duan
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology; D005353:Fibronectins / Q000378:metabolism; D007150:Immunohistochemistry; D053614:Janus Kinase 2 / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D046529:Microscopy, Electron, Transmission; D030421:Peroxynitrous Acid / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014527:Uric Acid / Q000494:pharmacology
chemical_list: D005353:Fibronectins; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D016212:Transforming Growth Factor beta; D030421:Peroxynitrous Acid; D014527:Uric Acid; C002744:3-nitrotyrosine; D014443:Tyrosine; D053614:Janus Kinase 2