Patients with Encapsulating Peritoneal Sclerosis Have Increased Peritoneal Expression of Connective Tissue Growth Factor (CCN2), Transforming Growth Factor-β1, and Vascular Endothelial Growth Factor

Abstract

IntroductionEncapsulating peritoneal sclerosis (EPS) is a devastating complication of peritoneal dialysis (PD). The pathogenesis is not exactly known and no preventive strategy or targeted medical therapy is available. CCN2 has both pro-fibrotic and pro-angiogenic actions and appears an attractive target. Therefore, we studied peritoneal expression of CCN2, as well as TGFβ1 and VEGF, in different stages of peritoneal fibrosis.Materials and methodsSixteen PD patients were investigated and compared to 12 hemodialysis patients and four pre-emptively transplanted patients. Furthermore, expression was investigated in 12 EPS patients in comparison with 13 PD and 12 non-PD patients without EPS. Peritoneal tissue was taken during kidney transplantation procedure or during EPS surgery. In a subset of patients, CCN2 protein levels in peritoneal effluent and plasma were determined. Samples were examined by qPCR, histology, immunohistochemistry, and ELISA.ResultsPeritoneal CCN2 expression was 5-fold higher in PD patients compared to pre-emptively transplanted patients (P<0.05), but did not differ from hemodialysis patients. Peritoneal expression of TGFβ1 and VEGF were not different between the three groups; neither was peritoneal thickness. Peritoneum of EPS patients exhibited increased expression of CCN2 (35-fold, P<0.001), TGFβ1 (24-fold, P<0.05), and VEGF (77-fold, P<0.001) compared to PD patients without EPS. In EPS patients, CCN2 protein was mainly localized in peritoneal endothelial cells and fibroblasts. CCN2 protein levels were significantly higher in peritoneal effluent of EPS patients compared to levels in dialysate of PD patients (12.0±4.5 vs. 0.91±0.92 ng/ml, P<0.01), while plasma CCN2 levels were not increased.ConclusionsPeritoneal expression of CCN2, TGFβ1, and VEGF are significantly increased in EPS patients. In early stages of peritoneal fibrosis, only CCN2 expression is slightly increased. Peritoneal CCN2 overexpression in EPS patients is a locally driven response. The potential of CCN2 as biomarker and target for CCN2-inhibiting agents to prevent or treat EPS warrants further study.

Buccal Mucosal Epithelial Cells Downregulate CTGF Expression in Buccal Submucosal Fibrosis Fibroblasts

“…Since CTGF is one of the primary early targets of TGF beta pathway, we used the early passage cells of SMF-F to examine the effect of such cells on CTGF levels under co-culture conditions. Further, increased expression of CTGF is one of the well-known factors in several fibrotic diseases, besides increased expression of TGF beta and VEGF [20][21][22][23][24].…”

Parenchyma–stromal interactions induce fibrosis by secreting CCN2 and promote osteoclastogenesis by stimulating RANKL and CD68 through activated TGF‐β/BMP4 in ameloblastoma

“…In CCN2-positive tumor areas (with fibrous-type stroma), TGFb expression was low to absent, whereas CCN2-negative tumor areas (with myxoid-type stroma) exhibited strong TGF-b expression. In fibrotic diseases, CCN2 is the key effector of the fibrogenic effects of TGF-b, but the precise mechanism of these concerted effects are ill-defined (9,21,23). Recent evidence suggests that CCN2 acts downstream of TGF-b as a co-operative mediator (8,(24)(25)(26)(27).…”

“…Transforming growth factor‐beta (TGF‐β) is a pleiotropic cytokine that regulates growth, cell motility, and differentiation . TGF‐β plays a dual role by influencing both tumor development and metastasis , and its deregulation has been implicated in various diseases including cancers and fibrosis . In ameloblastoma, TGF‐β putatively enhances the invasive phenotype .…”

MiR-200a ameliorates peritoneal fibrosis and functional deterioration in a rat model of peritoneal dialysis

“…Emerging evidence shows that high-glucose conditions of dialysate and inflammation factors elevate the expression of transforming growth factor beta 1 (TGF-β1), which is the main factor controlling fibrosis in all organs. TGF-β1 binds its receptor on the cell membrane and triggers the activation of Snail, Slug, and ZEB1-2, which play a role in repressing E-cadherin expression and inducing EMT [ 7 – 10 ]. However, as TGF-β1 is indispensable in maintaining homeostasis of the immune system, blocking the general effects of this pathway creates long-term problems [ 11 , 12 ].…”