Effect of potent redox-modulating manganese porphyrin, MnTM-2-PyP, on the Na⁺/H⁺ exchangers NHE-1 and NHE-3 in the diabetic rat

Authors: Khan, Islam¹; Batinic-Haberle, Ines²; Benov, Ludmil T.¹

Source: Redox Report, Volume 14, Number 6, December 2009 , pp. 236-242(7)

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Abstract:

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 NHE-3 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.

Keywords: DIABETES; MANGANESE PORPHYRIN; DIABETIC COMPLICATIONS; MNTM-2-PYP; SOD MIMIC; NA+/H+ EXCHANGER (NHE); OXIDATIVE STRESS; HYPERGLYCEMIA; DIABETIC NEPHROPATHY; ANTIOXIDANT

Document Type: Research Article

DOI: http://dx.doi.org/10.1179/135100009X12525712409698

Affiliations: 1: Department Biochemistry, Faculty of Medicine, Kuwait University, Safat, Kuwait 2: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, USA

Publication date: 2009-12-01

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