NF-kB overexpression and decreased immunoexpression of AR in the muscular layer is related to structural damages and apoptosis in cimetidine-treated rat vas deferens

Autor(es)

Koshimizu, Juliana Y. ^[1] ; Beltrame, Flavia L. ^[2] ; de Pizzol, Jr., Jose P. ^[1] ; Cerri, Paulo S. ^[1] ; Caneguim, Breno H. ^[1] ; Sasso-Cerri, Estela ^[1]

Afiliação do(s) autor(es)

^[1] UNESP, Araraquara Dent Sch, Lab Histol & Embryol, Dept Morphol, Jaboticabal, Estadual Paulis - Brazil

^[2] Fed Univ Sao Paulo Unifesp, Dept Morphol & Genet, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Reproductive Biology and Endocrinology; v. 11, APR 9 2013.
• Citações Web of Science: 14

Resumo

Background: Cimetidine, histamine H-2 receptors antagonist, has caused adverse effects on the male hormones and reproductive tract due to its antiandrogenic effect. In the testes, peritubular myoid cells and muscle vascular cells death has been associated to seminiferous tubules and testicular microvascularization damages, respectively. Either androgen or histamine H-2 receptors have been detected in the mucosa and smooth muscular layer of vas deferens. Thus, the effect of cimetidine on this androgen and histamine-dependent muscular duct was morphologically evaluated. Methods: The animals from cimetidine group (CMTG; n=5) received intraperitoneal injections of 100 mg/kg b.w. of cimetidine for 50 days; the control group (CG) received saline solution. The distal portions of vas deferens were fixed in formaldehyde and embedded in paraffin. Masson's trichrome-stained sections were subjected to morphological and the following morphometrical analyzes: epithelial perimeter and area of the smooth muscular layer. TUNEL (Terminal deoxynucleotidyl-transferase mediated dUTP Nick End Labeling) method, NF-kB (nuclear factor kappa B) and AR (androgen receptors) immunohistochemical detection were also carried out. The birefringent collagen of the muscular layer was quantified in picrosirius red-stained sections under polarized light. The muscular layer was also evaluated under Transmission Electron Microscopy (TEM). Results: In CMTG, the mucosa of vas deferens was intensely folded; the epithelial cells showed numerous pyknotic nuclei and the epithelial perimeter and the area of the muscular layer decreased significantly. Numerous TUNEL-labeled nuclei were found either in the epithelial cells, mainly basal cells, or in the smooth muscle cells which also showed typical features of apoptosis under TEM. While an enhanced NF-kB immunoexpression was found in the cytoplasm of muscle cells, a weak AR immunolabeling was detected in these cells. In CMTG, no significant difference was observed in the birefringent collagen content of the muscular layer in comparison to CG. Conclusions: Cimetidine induces significant damages in the epithelium; a possible antiandrogenic effect on the basal cells turnover should be considered. The cimetidine-induced muscle cells apoptosis confirms the susceptibility of these cells to this drug. The parallelism between enhanced cytoplasmic NF-kB immunolabeling in the damaged muscular tissue and muscle cell apoptosis suggests that this drug may avoid the translocation of NF-kB to the nucleus and interfere in the control of NF-kB-mediated smooth muscle cell apoptosis. The decreased immunoexpression of ARs verified in the damaged muscular tissue reinforces this possibility. (AU)

• Processo FAPESP: 09/17895-5 - Avaliação morfofuncional da espermatogônia tronco durante a espermatogênese sazonal de rãs-touro
• Beneficiário: Estela Sasso Cerri
• Linha de fomento: Auxílio à Pesquisa - Regular
• Processo FAPESP: 08/53288-3 - Avaliação morfológica e morfométrica de ducto deferente de ratos tratados com antagonista de receptores H2-Cimetidina
• Beneficiário: Juliana Yumi Koshimizu
• Linha de fomento: Bolsas no Brasil - Iniciação Científica
• Processo FAPESP: 06/54776-6 - Avaliação morfológica e morfométrica de testículos de ratos tratados com cimetidina, com ênfase na célula de Sertoli e na vascularização intersticial
• Beneficiário: Estela Sasso Cerri
• Linha de fomento: Auxílio à Pesquisa - Regular
• Processo FAPESP: 10/02409-5 - Aspectos histopatológicos do tecido intersticial de ratos tratados com cimetidina e participação da Vitamina B12 na reparação da espermatogênese
• Beneficiário: Flávia Luciana Beltrame
• Linha de fomento: Bolsas no Brasil - Doutorado