Effect of potent redox-modulating manganese porphyrin, MnTM-2-PyP, on the Na(+)/H(+) exchangers NHE-1 and NHE-3 in the diabetic rat.
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.
Khan
Islam
I
Department Biochemistry, Faculty of Medicine, Kuwait University, Safat, Kuwait.
Batinic-Haberle
Ines
I
Benov
Ludmil T
LT
D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D005649:Fumarate Hydratase / Q000378:metabolism; D006442:Glycated Hemoglobin / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D015227:Lipid Peroxidation; D008297:Male; D008665:Metalloporphyrins / Q000378:metabolism* / Q000494:pharmacology; D010084:Oxidation-Reduction; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D000074082:Sodium-Hydrogen Exchanger 1; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism
D000154:Aconitate Hydratase; D001786:Blood Glucose; D005649:Fumarate Hydratase; D006442:Glycated Hemoglobin; D008665:Metalloporphyrins; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D000074082:Sodium-Hydrogen Exchanger 1; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D013482:Superoxide Dismutase; C452850:Slc9a1 protein, rat; C000613387:Slc9a3 protein, rat; C520507:manganese tetrakis-(N-methyl-2 pyridyl) porphyrin