HGF and BMP-7 Ameliorate High Glucose–Induced Epithelial-to-Mesenchymal Transition of Peritoneal Mesothelium

Abstract

Over time, peritoneal dialysis results in functional and structural alterations of the peritoneal membrane, but the underlying mechanisms and whether these changes are reversible are not completely understood. Here, we studied the effects of high levels of glucose, which are found in the dialysate, on human peritoneal mesothelial cells (HPMCs). We found that high concentrations of glucose induced epithelialto-mesenchymal transition (EMT) of HPMC, suggested by decreased expression of E-cadherin and increased expression of ␣-smooth muscle actin, fibronectin, and type I collagen and by increased cell migration. Normalization of glucose concentration on day 2 reversed the phenotypic transformation, but the changes were irreversible after 7 d of stimulation with high glucose. In addition, exposure of HPMC to high glucose resulted in a decreased expression of the antifibrotic cytokines, hepatocyte growth factor (HGF) and bone morphogenic protein 7 (BMP-7). Exogenous treatment with HGF resulted in a dosage-dependent prevention of high glucose-induced EMT. Both BMP-7 peptide and gene transfection with an adenoviral vector of BMP-7 also protected HPMCs from EMT. Furthermore, adenoviral BMP-7 transfection decreased peritoneal EMT and ameliorated peritoneal thickening in an animal model of peritoneal dialysis. In summary, high concentrations of glucose induce a reversible EMT of HPMCs, associated with decreased production of HGF and BMP-7. Treatment of HPMCs with HGF or BMP-7 blocks high glucose-induced EMT, and BMP-7 ameliorates peritoneal fibrosis in an animal model of peritoneal dialysis.

Endoplasmic reticulum stress as a novel target to ameliorate epithelial-to-mesenchymal transition and apoptosis of human peritoneal mesothelial cells

“…We have already demonstrated a reversal of high-glucose-induced EMT upon the removal of high-glucose stimuli in HPMCs with an improvement of peritoneal thickening and fibrosis in an animal model of PD by peritoneal rest. 8 ER stress was not only a direct inducer of EMT of HPMCs but was also a mediator of TGF-β1-induced EMT in HPMCs. TGF-β1 is a representative pro-fibrotic cytokine that is known to induce peritoneal fibrosis through a phenotypic transition of peritoneal mesothelial cells.…”

“…The phenotypic transition of a peritoneal mesothelial cell to mesenchymal cell, the so-called EMT, has been recognized as an important mechanism of peritoneal fibrosis. 8,9 EMT in PD patients was associated with ultrafiltration failure, which highlighted the clinical significance of peritoneal EMT as a cause of peritoneal dysfunction. 5,6,41 ER stress has been implicated in EMT and fibroblast accumulation in organ fibrosis.…”

“…[4][5][6] Previous studies suggested that peritoneal mesothelial cells underwent phenotype transition, epithelial-to-mesenchymal transition (EMT), during the process of PD. [7][8][9][10][11] Because EMT is known to be a reversible process, it can be a therapeutic target for preserving peritoneal membrane function. 8,9,[11][12][13] In addition to EMT, apoptosis of the peritoneal mesothelial cells is also believed to be one of the early mechanisms of peritoneal damage.…”

“…[7][8][9][10][11] Because EMT is known to be a reversible process, it can be a therapeutic target for preserving peritoneal membrane function. 8,9,[11][12][13] In addition to EMT, apoptosis of the peritoneal mesothelial cells is also believed to be one of the early mechanisms of peritoneal damage. The accumulation of misfolded proteins and the induction of endoplasmic reticulum (ER) stress have been implicated in the development of phenotypic transition and apoptosis of epithelial cells.…”

Nano-sized carriers in gene therapy for peritoneal fibrosisin vivo

“…Intraperitoneal administration of adenoviral vectors expressing bone morphogenetic protein-7 (BMP-7), which is an anti-fibrotic molecule, was also shown to ameliorate peritoneal fibrosis in a rat model [36]. In that study, adenoviral vector-mediated BMP-7 delivery maintained increased expression levels of BMP-7 in the peritoneum for up to 14 days after administration [36], and inhibited mesothelial–mesenchymal transition of cultured human peritoneal mesothelial cells [36]. …”