Beneficial effects of L-arginine nitric oxide-producing pathway in rats treated with alloxan.
In an attempt to elucidate molecular mechanisms and factors involved in beta cell regeneration, we evaluated a possible role of the L-arginine-nitric oxide (NO)-producing pathway in alloxan-induced diabetes mellitus. Diabetes was induced in male Mill Hill rats with a single alloxan dose (120 mg kg(-1)). Both non-diabetic and diabetic groups were additionally separated into three subgroups: (i) receiving L-arginine . HCl (2.25%), (ii) receiving L-NAME . HCl (0.01%) for 12 days as drinking liquids, and (iii) control. Treatment of diabetic animals started after diabetes induction (glucose level > or = 12 mmol l(-1)). We found that disturbed glucose homeostasis, i.e. blood insulin and glucose levels in diabetic rats was restored after L-arginine treatment. Immunohistochemical findings revealed that L-arginine had a favourable effect on beta cell neogenesis, i.e. it increased the area of insulin-immunopositive cells. Moreover, confocal microscopy showed colocalization of insulin and pancreas duodenum homeobox-1 (PDX-1) in both endocrine and exocrine pancreas. This increase in insulin-expressing cells was accompanied by increased cell proliferation (observed by proliferating cell nuclear antigen-PCNA immunopositivity) which occurred in a regulated manner since it was associated with increased apoptosis (detected by the TUNEL method). Furthermore, L-arginine enhanced both nuclear factor-kB (NF-kB) and neuronal nitric oxide synthase (nNOS) immunopositivities. The effect of L-arginine on antioxidative defence was observed especially in restoring to control level the diabetes-induced increase in glutathione peroxidase activity. In contrast to L-arginine, diabetic pancreas was not affected by L-NAME supplementation. In conclusion, the results suggest beneficial L-arginine effects on alloxan-induced diabetes resulting from the stimulation of beta cell neogenesis, including complex mechanisms of transcriptional and redox regulation.
Vasilijevic
Ana
A
Department of Physiology, Institute for Biological Research, Sinia Stankovi, University of Belgrade, Bulevar Despota Stefana 142, 11060, Belgrade, Serbia.
Buzadzic
Biljana
B
Korac
Aleksandra
A
Petrovic
Vesna
V
Jankovic
Aleksandra
A
Korac
Bato
B
D000496:Alloxan; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001120:Arginine / Q000494:pharmacology*; D001786:Blood Glucose; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D020033:Protein Isoforms; D051381:Rats; D015534:Trans-Activators / Q000378:metabolism
D000975:Antioxidants; D001786:Blood Glucose; D018398:Homeodomain Proteins; D016328:NF-kappa B; D018809:Proliferating Cell Nuclear Antigen; D020033:Protein Isoforms; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D009569:Nitric Oxide; D000496:Alloxan; D001120:Arginine; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester
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