title: Tranilast attenuates the up-regulation of thioredoxin-interacting protein and oxidative stress in an experimental model of diabetic nephropathy.
abstract: BACKGROUND
  Diabetic nephropathy is the leading cause of kidney failure in the developed world. Tranilast has been reported to not only act as an anti-inflammatory and anti-fibrotic compound, but it also exerts anti-oxidative stress effects in diabetic nephropathy. Thioredoxin-interacting protein (Txnip) is the endogenous inhibitor of the anti-oxidant thioredoxin and is highly up-regulated in diabetic nephropathy, leading to oxidative stress and fibrosis. In this study, we aimed to investigate whether tranilast exerts its anti-oxidant properties through the inhibition of Txnip.
  
  
  METHODS
  Heterozygous Ren-2 rats were rendered diabetic with streptozotocin. Another group of rats were injected with citrate buffer alone and treated as non-diabetic controls. After 6 weeks of diabetes, diabetic rats were divided into two groups: one group gavaged with tranilast at 200 mg/kg/day and another group with vehicle.
  
  
  RESULTS
  Diabetic rats had a significant increase in albuminuria, tubulointerstitial fibrosis, peritubular collagen IV accumulation, reactive oxygen species (ROS) and macrophage infiltration (all P < 0.05). These changes were associated with an increase in Txnip mRNA and protein expression in the tubules and glomeruli of diabetic kidney. Treatment with tranilast for 4 weeks significantly attenuated Txnip up-regulation in diabetic rats and this was associated with a reduction in ROS, fibrosis and macrophage infiltration (all P < 0.05).
  
  
  CONCLUSIONS
  This is the first study to demonstrate that tranilast not only has anti-inflammatory and anti-fibrotic effects as previously reported but also attenuates the up-regulation of Txnip and oxidative stress in diabetic nephropathy.
authors.affiliation: The University of Melbourne, Department of Medicine, St. Vincent’s Hospital, VIC, Australia.
authors.forename: Sih Min
authors.initials: SM
authors.lastname: Tan
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Cox
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Kelly
authors.forename: Weier
authors.initials: W
authors.lastname: Qi
mesh_terms: D000419:Albuminuria / Q000209:etiology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D024141:Collagen Type IV / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000473:pathology; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis / Q000209:etiology / Q000473:pathology; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D049449:Luminescence; D008264:Macrophages / Q000378:metabolism; D009395:Nephritis, Interstitial / Q000209:etiology / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation; D062367:ortho-Aminobenzoates / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D024141:Collagen Type IV; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C493796:TXNIP protein, rat; D062367:ortho-Aminobenzoates; C012293:tranilast