期刊
EUROPEAN JOURNAL OF PHARMACOLOGY
卷 807, 期 -, 页码 12-20出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejphar.2017.04.026
关键词
Antioxidant; Kidney; ACE inhibitor; NADPH oxidase; Renal remodeling; Inflammation
资金
- Diabetes Australia
- Victorian Government of Australia's Operational Infrastructure
- National Health and Medical Research Council (NHMRC) of Australia [ID1059960]
- Department of Education Australia
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 (55 mg/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 (1.5 mM/kg/day subcutaneously, n=8), ramipril (1 mg/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, p47(Phox)), accompanied by an amelioration of diabetes-induced glomerular injury (podocin, nephrin, Kim-1), tubulo-interstitial fibrosis (TGF beta 1, TGF beta-R2, pSMAD3, alpha-SMA) and pro-inflammatory cytokines (TNF alpha, 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.
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