Olive leaf extract counteracts epithelial to mesenchymal transition process induced by peritoneal dialysis, through the inhibition of TGFβ1 signaling

Abstract

The mesothelial cells (MCs) play an important role in the morpho-functional alterations of the peritoneal membrane (PM) undergoing peritoneal dialysis (PD). MCs, through the epithelial-mesenchymal transition process (EMT), progressively acquire a myofibroblast-like phenotype, promoting peritoneal fibrosis (PF) and failure of peritoneal membrane function. Transforming growth factor β1 (TGFβ1), through canonical and non-canonical pathways, promotes the epithelial-mesenchymal transition (EMT) process leading to PF. To investigate the therapeutic potential of an olive leaf extract (OLE) on preserving peritoneal membrane function, we evaluated the effect of OLE on the TGFβ1-induced EMT in mesothelial cells, Met5A, and elucidated the underlying molecular mechanisms. As assessed by changes in the expression of epithelial, mesenchymal, and fibrotic cell markers (such as E-cadherin, N-cadherin, α-SMA, fibronectin, vimentin), levels of matrix metalloproteinases (MMP2 and MMP9), and cell migration, OLE inhibited the TGFβ1-induced EMT. Importantly, the beneficial effect of OLE was mediated by reduction of the TGFβ1-induced activation of Smad2/3 signaling and the mitigation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) phosphorylation. Smad/non-Smad signaling pathways, activated by TGFβ1, both reduce expression of epithelial marker E-cadherin which has a crucial role in EMT initiation. Interestingly, we observed that in presence of OLE activity of the E-cadherin, promoter was increased and concomitantly OLE reduced the nuclear content of its co-repressor SNAIL. Our results suggest the potential therapeutic of OLE to counteract fibrotic process in peritoneal dialysis patients.

Polyphenols Attenuate Highly-Glycosylated Haemoglobin-Induced Damage in Human Peritoneal Mesothelial Cells

“…It is widely known that polyphenols exert the anti-inflammatory action by different mechanisms: radical scavenging, metal chelating, NOS inhibition, inhibition of certain enzymes involved in ROS production, and upregulation of endogenous antioxidant enzymes [ 42 , 75 , 76 , 77 , 80 ]. This work is in agreement with previous studies, which support the preventive effects of polyphenols on inflammation in different diseases [ 39 , 48 , 82 , 83 , 84 ], including the kidney in animal models [ 85 ] or in vivo models of study, where active compounds extracted from extra olive oil (oil phenols) counteract mesothelial to mesenchymal transition of HPMCs exposed to conventional peritoneal dialysate in vitro and in vivo, preventing and counteracting the development of peritoneal fibrosis during PD [ 86 , 87 ]. These data are consistent with the results obtained by other groups, for example, when immortalized human mesothelial cells (Met5A) were exposed either to the regular growth medium, to standard acidic lactate-buffered PDF (Dianeal PD4), or to a more biocompatible lactate-bicarbonate-buffered PDF (Physioneal 40).…”

Asiaticoside inhibits TGF-β1-induced mesothelial-mesenchymal transition and oxidative stress via the Nrf2/HO-1 signaling pathway in the human peritoneal mesothelial cell line HMrSV5

“…Many TGF-β1 blockers are used for anti-MMT action in vivo and vitro, such as TGF-β1 receptor blocker and neutralizing antibody. In the last years, many authors have focused on the beneficial effects of natural herbs or their active ingredients on maintaining peritoneal integrity [19,20]. But none of them have been used clinically, and the safety is unknown.…”

Loosening of the mesothelial barrier as an early therapeutic target to preserve peritoneal function in peritoneal dialysis

“…Although the presence of peritoneal EMT and its mechanism have been extensively studied, there are not many studies showing the beneficial effect of therapy targeting peritoneal EMT per se. Table 1 shows the previous studies regarding EMT-targeting interventions using in vitro and in vivo experimental models [21,[25][26][27]51,[56][57][58][59][60][61][62][63][64].…”