The superoxide dismutase mimetic tempol blunts diabetes-induced upregulation of NADPH oxidase and endoplasmic reticulum stress in a rat model of diabetic nephropathy.
Endoplasmic reticulum (ER) stress contributes to progression of diabetic nephropathy, which promotes end-stage renal failure in diabetic patients. This study was undertaken to investigate the actions of tempol and ramipril, pharmacological agents that target the consequences of NADPH oxidase, on diabetic nephropathy in a rat model of type 1 diabetes, with an emphasis on markers of ER stress. Male Sprague-Dawley rats were injected intravenously with a single bolus of streptozotocin (55mg/kg) to induce type 1 diabetes. An additional age-matched group of rats was administered with citrate vehicle as controls. After 4 weeks of untreated diabetes, rats received tempol (1.5mM/kg/day subcutaneously, n=8), ramipril (1mg/kg/day in drinking water, n=8) or remained untreated for an additional 4 weeks (n=7). After 8 weeks of diabetes in total, kidneys were collected for histological analysis, gene expression and protein abundance. Tempol and ramipril blunted diabetes-induced upregulation of NADPH oxidase isoforms (Nox4, Nox2, p47phox), accompanied by an amelioration of diabetes-induced glomerular injury (podocin, nephrin, Kim-1), tubulo-interstitial fibrosis (TGFβ1, TGFβ-R2, pSMAD3, α-SMA) and pro-inflammatory cytokines (TNFα, MCP-1, ANX-A1, FPR2) expression. In addition, the diabetes-induced renal ER stress, evidenced by increased expression of GRP-78 chaperone and stress-associated markers ATF4, TRB3, as well as XBP1s, phospho-p38 mitogen-activated protein kinase (MAPK) and 3-nitrotyrosination, were all attenuated by tempol and ramipril. These observations suggest that antioxidant approaches that blunt NADPH upregulation may attenuate diabetic nephropathy, at least in part by negatively regulating ER stress and inflammation, and hence ameliorating kidney damage.
['De Blasio|Miles J|MJ|', 'Ramalingam|Anand|A|', 'Cao|Anh H|AH|', 'Prakoso|Darnel|D|', 'Ye|Ji-Ming|JM|', 'Pickering|Raelene|R|', 'Watson|Anna M D|AMD|', 'de Haan|Judy B|JB|', 'Kaye|David M|DM|', 'Ritchie|Rebecca H|RH|']
D000818:Animals D040761:Biomimetic Materials D003497:Cyclic N-Oxides D003928:Diabetic Nephropathies D004195:Disease Models, Animal D059865:Endoplasmic Reticulum Stress D005355:Fibrosis D007678:Kidney Glomerulus D007684:Kidney Tubules D008297:Male D019255:NADPH Oxidases D009569:Nitric Oxide D018384:Oxidative Stress D017257:Ramipril D051381:Rats D017207:Rats, Sprague-Dawley D013113:Spin Labels D013482:Superoxide Dismutase D015854:Up-Regulation
NADPH oxidase Kidney Antioxidant Inflammation ACE inhibitor Renal remodeling