HGF and BMP-7 ameliorate high glucose-induced epithelial-to-mesenchymal transition of peritoneal mesothelium.
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 epithelial-to-mesenchymal transition (EMT) of HPMC, suggested by decreased expression of E-cadherin and increased expression of alpha-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.
Yu
Min-A
MA
Division of Nephrology, Ewha University School of Medicine, Yangchun-Ku, Seoul, Korea.
Shin
Kyung-Sook
KS
Kim
Jung Hye
JH
Kim
Yong-Il
YI
Chung
Soon Sup
SS
Park
Sun-Hee
SH
Kim
Yong-Lim
YL
Kang
Duk-Hee
DH
D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D055419:Bone Morphogenetic Protein 7 / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005353:Fibronectins / Q000235:genetics; D005947:Glucose / Q000008:administration & dosage / Q000494:pharmacology*; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008648:Mesoderm / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D023421:Models, Animal; D010530:Peritoneal Dialysis / Q000009:adverse effects; D010537:Peritoneum / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection
C541116:ACTA2 protein, human; D000199:Actins; D055419:Bone Morphogenetic Protein 7; D015820:Cadherins; D024042:Collagen Type I; D005353:Fibronectins; D012333:RNA, Messenger; D017228:Hepatocyte Growth Factor; D005947:Glucose