Tranilast attenuates the up-regulation of thioredoxin-interacting protein and oxidative stress in an experimental model of diabetic nephropathy.
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.
Tan
Sih Min
SM
The University of Melbourne, Department of Medicine, St. Vincent’s Hospital, VIC, Australia.
Zhang
Yuan
Y
Cox
Alison J
AJ
Kelly
Darren J
DJ
Qi
Weier
W
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*
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