TGF-β1-VEGF-A pathway induces neoangiogenesis with peritoneal fibrosis in patients undergoing peritoneal dialysis

Abstract

The characteristic features of chronic peritoneal injury with peritoneal dialysis (PD) are submesothelial fibrosis and neoangiogenesis. Transforming growth factor (TGF)β and vascular endothelial growth factor (VEGF)-A are the main mediators of fibrosis and neoangiogenesis, respectively; however, the effect of the interaction between them on the peritoneum is not well known. In this study, we investigated the relationship between TGF-β1 and VEGF-A in inducing peritoneal fibrosis by use of human tissues and dialysate, cultured cells, and animal models. The VEGF-A concentration correlated with the dialysate-to-plasma ratio of creatinine (D/P Cr) ( P < 0.001) and TGF-β1 ( P < 0.001) in human PD effluent. VEGF-A mRNA levels increased significantly in the peritoneal tissues of human ultrafiltration failure (UFF) patients and correlated with number of vessels ( P < 0.01) and peritoneal thickness ( P < 0.001). TGF-β1 increased VEGF-A production in human mesothelial cell lines and fibroblast cell lines, and TGF-β1-induced VEGF-A was suppressed by TGF-β receptor I (TGFβR-I) inhibitor. Incremental peak values of VEGF-A mRNA stimulated by TGF-β1 in human cultured mesothelial cells derived from PD patients with a range of peritoneal membrane functions correlated with D/P Cr ( P < 0.05). To evaluate the regulatory mechanisms of VEGF-A and neoangiogenesis in vivo, we administered TGFβR-I inhibitor intraperitoneally in a rat chlorhexidine-induced peritoneal injury (CG) model. TGFβR-I inhibitor administration in the CG model decreased peritoneal thickness ( P < 0.001), the number of vessels ( P < 0.001), and VEGF-A levels ( P < 0.05). These results suggest that neoangiogenesis is associated with fibrosis through the TGF-β1-VEGF-A pathway in mesothelial cells and fibroblasts. These findings are important when considering the strategy for management of UFF in PD patients.

The Complex Morphopathogenetic Aspects of Intraabdominal Adhesions Development and Course in Infants. Summary of the Doctoral Thesis

“…Excess of TGFβ correlates with an increased upbuilt of connective tissue (Verrecchia & Mauviel, 2007). A statistically significant moderately strong negative correlation between TGFβ and VEGF was observed, indicating the suppression of VEGF under the impact of TGFβ in intraabdominal adhesion tissues, which might be a compensatory mechanism in the morphopathogenesis of intraabdominal tissues.The findings of the current study is consistent with other author's data on TGFβ un VEGF interaction and involvement in peritoneal damage and fibrosis development(Kariya et al, 2018). TGFβ is responsible for VEGF structure protein stability and can also inhibit its expression, therefore regulating angiogenesis(Geng et al, 2013).A negative correlation between TGFβ and MMP-2 findings was observed, which is consistent with the literature.…”

Itraconazole Attenuates Peritoneal Fibrosis Through Its Effect on the Sonic Hedgehog Signaling Pathway in Mice

“…Since peritoneal fibrosis can cause ultrafiltration failure, it is important to understand the effect of itraconazole treatment on peritoneal function. Considering the changes in TGF-β1 in our results, itraconazole treatment can be expected to have a significant effect on peritoneal function [35,36]. We are going to assess this aspect in our future study.…”

Reconstruction of the urinary tract at the appropriate time reduces fibrosis of the metanephros in rats as judged by imaging

“…One report suggests that the metanephros is provided with a spatial direction for capillary development by VEGF [34] and may be involved in the vasculature identified around the MNB. However, it must be considered that VEGF is also involved in fibrosis, which promotes the growth of grafts and may further exacerbate fibrosis during hydronephrosis [35,36]. In the unilateral ureteric obstruction (UUO) model of progressive injury, an angiogenic response was observed early and the endothelial cells proliferated; however, this led to endothelial cell loss after the 4 th day [37].…”