期刊
REDOX REPORT
卷 14, 期 6, 页码 236-242出版社
TAYLOR & FRANCIS LTD
DOI: 10.1179/135100009X12525712409698
关键词
diabetes; hyperglycemia; oxidative stress; manganese porphyrin; SOD mimic; MnTM-2-PyP; antioxidant; diabetic complications; diabetic nephropathy; Na+/H+ exchanger (NHE)
资金
- Kuwait University [MB 07/04]
- HSC Research Core Facility [GM01/01]
- NIH [U19 AI67798]
- Wallace H Coulter Translational Partners [NIH-IR21-ESO/3682]
Increased expression of Na+/H+ exchanger (NHE) and Na+, K+-ATPase activity have been demonstrated in diabetic nephropathy and are implicated in the development of hypertension. The aim of this study was to investigate the effect of a synthetic manganese porphyrin SOD mimic and peroxynitrite scavenger, Mn(III) 5,10,15,20-tetrakis(N-methylpyridinium-2-yl) porphyrin (MnTM-2-PyP) on the expression of NHE and Na+, K+-ATPase activity in the kidneys of streptozotocin (STZ) diabetic rats. MnTM-2-PyP administration (1 mg/kg/day) started immediately after STZ and lasted 2 months. Glucose and glycosylated hemoglobin levels were measured in blood. NHE-1 and NHE3 isoform expression, Na+, K+-ATPase activity, and markers of ROS/RNS-induced damage were determined in kidney homogenates. Diabetes caused lipid peroxidation, inactivation of aconitase, and increase of nitrotyrosine, which paralleled an increase in NHE-1 and NHE-3 expression and Na+, K+-ATPase activity. MnTM-2-PyP treatment had no effect on blood glucose and glycosylated hemoglobin, but suppressed lipid peroxidation and nitrotyrosine, protected aconitase against inactivation, and reversed the induction of NHE-1 and NHE-3 isoforms. Na+/H+ exchanger is under the control of redox-based cellular transcriptional activity, including members of the SP family of transcription factors. Mn(III) alkylpyridylporphyrins were previously found to inhibit activation of major transcription factors, including SP-1 via scavenging of signaling ROS/RNS. Therefore, our data suggest that, by reducing the levels of ROS/RNS, MnTM-2-PyP might interfere with signaling pathways responsible for NHE up-regulation.
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