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Immunolocalization of Advanced Glycation End Products, Mitogen Activated Protein Kinases, and Transforming Growth Factor-?/Smads in Pelvic Organ Prolapse.

ABSTRACT: Collagen and matrix metalloproteinases (MMP) play a pivotal role in the pathophysiology of Pelvic Organ Prolapse (POP) as a switch between type I and III collagen together with a simultaneous activation of MMPs have been observed in the vaginal wall. The aim of this study was to evaluate the Advanced Glycation End (AGE) products, ERK1/2 and transforming growth factor (TGF)-?/Smad pathway expression in muscularis propria in women with POP compared with control patients. We examined 20 patients with POP and 10 control patients treated for uterine fibromatosis. Immunohistochemical analysis using AGE, RAGE, ERK1/2, Smads-2/3, Smad-7, MMP-3, and collagen I-III, TIMP, and ?-SMA were performed. Smad-2/3, Smad-7, AGE, ERK1/2, p-ERK, and p-Smad3 were also evaluated using Western-blot analysis. POP samples from the anterior vaginal wall showed disorganization of the normal muscularis architecture. In POP samples, AGE, ERK1/2, Smad-2/3, MMP-3, and collagen III were upregulated in muscularis whereas in controls, Smad-7 and collagen I were increased. The receptor for AGEs (RAGE) was mild or absent both in controls and prolapse. We demonstrated the involvement of these markers in women with POP but further studies are required to elucidate if the overexpression of these molecules could play a crucial role in the pathophysiology of POP disease.

SUBMITTER: Vetuschi A

PROVIDER: S-EPMC6116086 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Immunolocalization of Advanced Glycation End Products, Mitogen Activated Protein Kinases, and Transforming Growth Factor-β/Smads in Pelvic Organ Prolapse.

Vetuschi Antonella A Pompili Simona S Gallone Anna A D'Alfonso Angela A Carbone Maria Gabriella MG Carta Gaspare G Festuccia Claudio C Gaudio Eugenio E Colapietro Alessandro A Sferra Roberta R

The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 20180508 9

Collagen and matrix metalloproteinases (MMP) play a pivotal role in the pathophysiology of Pelvic Organ Prolapse (POP) as a switch between type I and III collagen together with a simultaneous activation of MMPs have been observed in the vaginal wall. The aim of this study was to evaluate the Advanced Glycation End (AGE) products, ERK1/2 and transforming growth factor (TGF)-β/Smad pathway expression in muscularis propria in women with POP compared with control patients. We examined 20 patients wi ...[more]

PMID: 29737911

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Project description:ObjectiveThe aims of this study are to detect levels of AGEs and RAGE and SNPs for RAGE in vaginal tissues of women with POP and rats in a repair location, and to explore the relationship between AGEs-RAGE pathway and POP.MethodsThis study involved human vaginal tissues in fornix from 44 women with POP and 46 women without POP who were assigned to pelvic floor reconstruction or LAVH. The proteins of AGEs, collagen I, and RAGE were detected by immunohistochemistry and Western blot with appropriate primary antibodies. The entire RAGE gene of 24 women with POP and 25 controls were sequenced, and SNPs within were detected. Then, sixty 8-week-old female Sprague-Dawley rats subjected to abdominal defect were divided into three surgical pelvic floor reconstruction repair groups (n=20/group): A, repair with non-absorable prolene mesh; B, repair with absorbable SIS mesh; and C, a no repair control group. 3, 9, 15, and 21 months after operation, rats were sacrificed and the expression of AGEs, RAGE and collagen I in the tissues of repair location were detected in the various experimental groups. Statistical analysis included comparison of means (Student's t-test) and proportions (Chi-square test or Fisher test).ResultsBy both immunohistochemistry and Western blot, patients with POP showed higher protein expression of AGEs of POP than controls (P<0.05). In contrast, the expression of collagen I was lower in POP patients than in the control group (P<0.05). No differences in the expression of RAGE between the POP patients and controls were observed (P>0.05). In POP patients, the expression of collagen I decreased particularly in patients≥60 years old (P<0.05), but there were no different in the expression of AGEs and RAGE dependent on age (P>0.05). RAGE gene sequence variance analysis identified 18 variable loci, but only two of these were potential SNPs: rs184003 (1806), rs55640627 (2346) (P<0.05). Both rs184003 and rs55640627 are both intronic variants, indicating that they may not influence the structure of RAGE. In rat surgical repair model, group B showed a greater extent of abdominal prolapse than groups A and C (P<0.05). Consistent with this, the expression of AGEs in group B was higher than groups A and C (P<0.05), and collagen I in group B was lower than the two others, further supporting our notion that AGEs are inversely related to type I collagen content.ConclusionsIn summary, this study demonstrates that AGEs and RAGE might play important roles in the physiopathology of POP. Further studies are required to explore mechanisms of how AGEs-RAGE pathway may contribute to tissue degeneration and fragility in POP.

Project description:BackgroundPelvic organ prolapse (POP) is a common degenerative disease among females. We previously reported that advanced glycation end products (AGEs), compounds derived from nonenzymatic glycoxidation reactions, accumulated in the human vaginal wall and impaired the function of fibroblasts in the pathogenesis of POP. This study investigated the apoptosis induced by AGEs in human uterosacral ligament fibroblasts and the underlying mechanism.MethodsHuman uterosacral ligament fibroblasts were cultured and identified. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis was performed to identify the expression of miR-4429, phosphatase and tensin homolog (PTEN), and caspase-3. Flow cytometric analysis was applied to detect the apoptosis rate of fibroblasts. Dual-luciferase reporter assay was performed to verify the relationship between miR-4429 and PTEN. The overexpression of miR-4429 and the inhibition of PTEN were achieved by cell transfections. Western blot analysis was used to detect the protein levels of PTEN, phosphoinositide 3-kinase (PI3K), and protein kinase B (Akt).ResultsThe AGEs promoted fibroblast apoptosis both in the POP and the non-POP groups. The expression of PTEN increased in fibroblasts from the POP group or fibroblasts treated with AGEs. It was confirmed that miR-4429 interacted with PTEN messenger RNA (mRNA), and the expression level of miR-4429 was reduced in fibroblasts from the POP group or fibroblasts treated with AGEs. Further, overexpression of miR-4429 alleviated increased PTEN expression and fibroblast apoptosis induced by AGEs. Similarly, inhibition of PTEN expression alleviated increased fibroblast apoptosis induced by AGEs. In addition, the protein expressions of PI3K and phosphorylated Akt were reduced in fibroblasts exposed to AGEs.ConclusionsWe proposed that AGEs induced fibroblast apoptosis by regulating the miR-4429/PTEN/PI3K/Akt pathway in POP. Our results revealed a novel mechanism by which AGEs contributed to the molecular pathological alteration in POP.

Dataset Information

Immunolocalization of Advanced Glycation End Products, Mitogen Activated Protein Kinases, and Transforming Growth Factor-?/Smads in Pelvic Organ Prolapse.

Publications

Immunolocalization of Advanced Glycation End Products, Mitogen Activated Protein Kinases, and Transforming Growth Factor-β/Smads in Pelvic Organ Prolapse.

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