title: Effects of an Antimutagenic 1,4-Dihydropyridine AV-153 on Expression of Nitric Oxide Synthases and DNA Repair-related Enzymes and Genes in Kidneys of Rats with a Streptozotocin Model of Diabetes Mellitus.
abstract: Development of complications of diabetes mellitus (DM), including diabetic nephropathy, is a complex multi-stage process, dependent on many factors including the modification of nitric oxide (NO) production and an impaired DNA repair. The goal of this work was to study in vivo effects of 1,4-dihydropyridine AV-153, known as antimutagen and DNA binder, on the expression of several genes and proteins involved in NO metabolism and DNA repair in the kidneys of rats with a streptozotocin (STZ)-induced model of DM. Transcription intensity was monitored by means of real-time RT-PCR and the expression of proteins by immunohistochemistry. Development of DM significantly induced PARP1 protein expression, while AV-153 (0.5 mg/kg) administration decreased it. AV-153 increased the expression of Parp1 gene in the kidneys of both intact and diabetic animals. Expression of H2afx mRNA and γH2AX histone protein, a marker of DNA breakage, was not changed in diabetic animals, but AV-153 up-regulated the expression of the gene without any impact on the protein expression. Development of DM was followed by a significant increase in iNOS enzyme expression, while AV-153 down-regulated the enzyme expression up to normal levels. iNos gene expression was also found to be increased in diabetic animals, but unlike the protein, the expression of mRNA was found to be enhanced by AV-153 administration. Expression of both eNOS protein and eNos gene in the kidneys was down-regulated, and the administration of AV-153 normalized the expression level. The effects of the compound in the kidneys of diabetic animals appear to be beneficial, as a trend for the normalization of expression of NO synthases is observed.
authors.affiliation: Latvian Institute of Organic Synthesis, Riga, Latvia. kristine.osina@gmail.com.|Genomics and Bioinformatics, Institute of Biology of the University of Latvia, Salaspils, Latvia. kristine.osina@gmail.com.
authors.forename: Kristīne
authors.initials: K
authors.lastname: Ošiņa
authors.affiliation: Latvian Institute of Organic Synthesis, Riga, Latvia.|Faculty of Medicine, University of Latvia, Riga, Latvia.
authors.forename: Evita
authors.initials: E
authors.lastname: Rostoka
authors.affiliation: Latvian Institute of Organic Synthesis, Riga, Latvia.|Faculty of Medicine, University of Latvia, Riga, Latvia.
authors.forename: Sergejs
authors.initials: S
authors.lastname: Isajevs
authors.affiliation: Latvian Institute of Organic Synthesis, Riga, Latvia.|Faculty of Medicine, University of Latvia, Riga, Latvia.
authors.forename: Jelizaveta
authors.initials: J
authors.lastname: Sokolovska
authors.affiliation: Latvian Institute of Organic Synthesis, Riga, Latvia.|Genomics and Bioinformatics, Institute of Biology of the University of Latvia, Salaspils, Latvia.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Sjakste
authors.affiliation: Latvian Institute of Organic Synthesis, Riga, Latvia.|Faculty of Medicine, University of Latvia, Riga, Latvia.
authors.forename: Nikolajs
authors.initials: N
authors.lastname: Sjakste
mesh_terms: D000818:Animals; D016587:Antimutagenic Agents / Q000494:pharmacology*; D004260:DNA Repair / Q000187:drug effects*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004095:Dihydropyridines / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D006657:Histones / Q000378:metabolism; D007668:Kidney / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D009525:Niacin / Q000031:analogs & derivatives* / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013311:Streptozocin
chemical_list: D016587:Antimutagenic Agents; D004095:Dihydropyridines; D006657:Histones; D010750:Phosphoproteins; D012333:RNA, Messenger; C577575:gamma-H2AX protein, rat; C506181:sodium 3,5-bis-ethoxycarbonyl-2,6,dimethyl-1,4-dihydropyridine-4-carboxylate; D009525:Niacin; D013311:Streptozocin; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1