Rapamycin Protects from Type-I Peritoneal Membrane Failure Inhibiting the Angiogenesis, Lymphangiogenesis, and Endo-MT

Abstract

Preservation of peritoneal membrane (PM) is essential for long-term survival in peritoneal dialysis (PD). Continuous presence of PD fluids (PDF) in the peritoneal cavity generates chronic inflammation and promotes changes of the PM, such as fibrosis, angiogenesis, and lymphangiogenesis. Mesothelial-to-mesenchymal transition (MMT) and endothelial-to-mesenchymal transition (Endo-MT) seem to play a central role in this pathogenesis. We speculated that Rapamycin, a potent immunosuppressor, could be beneficial by regulating blood and lymphatic vessels proliferation. We demonstrate that mice undergoing a combined PD and Rapamycin treatment (PDF + Rapa group) presented a reduced PM thickness and lower number of submesothelial blood and lymphatic vessels, as well as decreased MMT and Endo-MT, comparing with their counterparts exposed to PD alone (PDF group). Peritoneal water transport in the PDF + Rapa group remained at control level, whereas PD effluent levels of VEGF, TGF-β, and TNF-α were lower than in the PDF group. Moreover, the treatment of mesothelial cells with Rapamycin in vitro significantly decreased VEGF synthesis and selectively inhibited the VEGF-C and VEGF-D release when compared with control cells. Thus, Rapamycin has a protective effect on PM in PD through an antifibrotic and antiproliferative effect on blood and lymphatic vessels. Moreover, it inhibits Endo-MT and, at least partially, MMT.

Analysis of mTOR pathway expression in lymphatic malformation and related diseases

“…The mTOR pathway is involved in various pathological mechanisms of lymphangiogenesis, lymphatic metastasis and several cancer developments, including colorectal cancer, gastric cancer, liver cancer, breast cancer and uterine cancer 15–17 . Sirolimus known as a mTOR inhibitor has an antiproliferative effect on lymphatic vessels, and is clinically used for a difficult‐to‐treat lymphatic anomalies 12,13,18–20 . Sirolimus binds the FK‐binding protein 12, resulting in a complex that prevents phosphorylation and activation of 4EBP1 and S6K1 21,22 .…”

Angiogenesis and Lymphangiogenesis in Peritoneal Dialysis

“…Additionally, there are other cell populations in the peritoneum that may also undergo a mesenchymal transition and collaborate in fibrotic diseases and specifically in PD-related fibrosis, as inflammatory bone marrow-derived circulating cells (fibrocytes), that could represent a 34% of total FSP1 + fibroblasts, and endothelial cells from blood vessels (endo-MT) (approximately 5%) [27,[29][30][31][32][33]. Besides TGF-β, it has been shown that endothelin-1 (ET-1) may also participate in endo-MT [28].…”

“…Nevertheless, it has to be taken into account that MMT is a physiologic process necessary for wound healing during PD. Another possibility is to act on the consequences of MMT or mesenchymal transition of other cells populations instead, such as the increased angiogenesis or lymphangiogenesis [33,47]. The therapeutic options tested until the date are exposed below in detail and summarized in Table 2.…”

“…In fact, it has been observed in hypoxic cells that rapamycin can interfere with HIF-1α activation by increasing the rate of its degradation [123]. Moreover, the anti-angiogenic activity of rapamycin is also due to the decrease in VEGF expression both in vitro and in vivo [33,124], and to the reduction in the response of vascular endothelial cells to stimulation by VEGF [124].…”

The Peritoneum: Health, Disease, and Perspectives regarding Tissue Engineering and Cell Therapies

“…Immunosuppressors, such as rapamycin, reduced peritoneum thickness, EMT by MCs, and levels of VEGF, TGF-β, and TNF-α [Gonzalez-Mateo et al, 2015]. In a rat model of encapsulating peritoneal sclerosis, intraperitoneal transplantation of human umbilical mesenchymal stem cells prevented peritoneal inflammation and fibrosis, suggesting a novel approach for cell therapy to peritoneal disorders [Fan et al, 2016].…”