Dataset Information

Endothelial Cell-Specific Molecule 1 Promotes Endothelial to Mesenchymal Transition in Renal Fibrosis.

ABSTRACT: The endothelial-to-mesenchymal transition (EndoMT) is involved in the complex pathogenesis of renal fibrosis. The soluble proteoglycan endothelial cell-specific molecule 1 (ESM1) is significantly upregulated in many tumor cells and cirrhosis-related disease. The role of ESM1 in renal fibrosis is unknown. This study investigates the role of ESM1 in renal fibrosis, using an in vivo unilateral ureteral obstruction (UUO) mouse model of renal fibrosis and in vitro mouse kidney MES 13 cells overexpressing ESM1. We observed that ESM1 overexpression significantly increased the motility and migration of MES 13 cells, independent of cell viability. In ESM1-overexpressing MES 13 cells, we also observed elevated expression of mesenchymal markers (N-cadherin, vimentin, matrix metallopeptidase 9 (MMP9)) and the fibrosis marker ?-smooth muscle actin (?-SMA) and decreased expression of the endothelial marker vascular endothelial cadherin (VE-cadherin) and CD31. In a mouse model of fibrosis induced by unilateral ureter obstruction, we observed time-dependent increases in ESM1, ?-SMA, and vimentin expression and renal interstitial collagen fibers in kidney tissue samples. These results suggest that ESM1 may serve as an EndoMT marker of renal fibrosis progression.

SUBMITTER: Hung TW

PROVIDER: S-EPMC7472197 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Endothelial Cell-Specific Molecule 1 Promotes Endothelial to Mesenchymal Transition in Renal Fibrosis.

Hung Tung-Wei TW Chu Chao-Yang CY Yu Chen-Lin CL Lee Chu-Che CC Hsu Li-Sung LS Chen Yong-Syuan YS Hsieh Yi-Hsien YH Tsai Jen-Pi JP

Toxins 20200806 8

The endothelial-to-mesenchymal transition (EndoMT) is involved in the complex pathogenesis of renal fibrosis. The soluble proteoglycan endothelial cell-specific molecule 1 (ESM1) is significantly upregulated in many tumor cells and cirrhosis-related disease. The role of ESM1 in renal fibrosis is unknown. This study investigates the role of ESM1 in renal fibrosis, using an in vivo unilateral ureteral obstruction (UUO) mouse model of renal fibrosis and in vitro mouse kidney MES 13 cells overexpres ...[more]

PMID: 32781625

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Project description:Intraflagellar transport protein 88 (Ift88) is required for ciliogenesis and shear stress-induced dissolution of cilia in embryonic endothelial cells coincides with endothelial-to-mesenchymal transition (EndMT) in the developing heart. EndMT is also suggested to underlie heart and lung fibrosis, however, the mechanism linking endothelial Ift88, its effect on EndMT and organ fibrosis remains mainly unexplored. We silenced Ift88 in endothelial cells (ECs) in vitro and generated endothelial cell-specific Ift88-knockout mice (Ift88endo) in vivo to evaluate EndMT and its contribution towards organ fibrosis, respectively. Ift88-silencing in ECs led to mesenchymal cells-like changes in endothelial cells. The expression level of the endothelial markers (CD31, Tie-2 and VE-cadherin) were significantly reduced with a concomitant increase in the expression level of mesenchymal markers (αSMA, N-Cadherin and FSP-1) in Ift88-silenced ECs. Increased EndMT was associated with increased expression of profibrotic Collagen I expression and increased proliferation in Ift88-silenced ECs. Loss of Ift88 in ECs was further associated with increased expression of Sonic Hedgehog signaling effectors. In vivo, endothelial cells isolated from the heart and lung of Ift88endo mice demonstrated loss of Ift88 expression in the endothelium. The Ift88endo mice were born in expected Mendelian ratios without any adverse cardiac phenotypes at baseline. Cardiac and pulmonary endothelial cells isolated from the Ift88endo mice demonstrated signs of EndMT and bleomycin treatment exacerbated pulmonary fibrosis in Ift88endo mice. Pressure overload stress in the form of aortic banding did not reveal a significant difference in cardiac fibrosis between Ift88endo mice and control mice. Our findings demonstrate a novel association between endothelial cilia with EndMT and cell proliferation and also show that loss of endothelial cilia-associated increase in EndMT contributes specifically towards pulmonary fibrosis.

Project description:Macroautophagy/autophagy plays a vital role in the homeostasis of diverse cell types. Vascular endothelial cells contribute to vascular health and play a unique role in vascular biology. Here, we demonstrated that autophagy defects in endothelial cells induced IL6 (interleukin 6)-dependent endothelial-to-mesenchymal transition (EndMT) and organ fibrosis with metabolic defects in mice. Inhibition of autophagy, either by a specific inhibitor or small interfering RNA (siRNA) for ATG5 (autophagy related 5), in human microvascular endothelial cells (HMVECs) induced EndMT. The IL6 level was significantly higher in ATG5 siRNA-transfected HMVECs culture medium compared with the control HMVECs culture medium, and neutralization of IL6 by a specific antibody completely inhibited EndMT in ATG5 siRNA-transfected HMVECs. Similar to the in vitro data, endothelial-specific atg5 knockout mice (Atg5 Endo; Cdh5-Cre Atg5 flox/flox mice) displayed both EndMT-associated kidney and heart fibrosis when compared to littermate controls. The plasma level of IL6 was higher in Atg5 Endo compared to that of control mice, and fibrosis was accelerated in Atg5 Endo treated with a HFD; neutralization of IL6 by a specific antibody inhibited EndMT and fibrosis in HFD-fed Atg5 Endo associated with the amelioration of metabolic defects. These results revealed the essential role of autophagy in endothelial cell integrity and revealed that the disruption of endothelial autophagy could lead to significant pathological IL6-dependent EndMT and organ fibrosis. Abbreviations: 3-MA: 3-methyladenine; ATG5: autophagy related 5; EndMT: endothelial-to-mesenchymal transition; HES: hematoxylin and eosin stain; HFD: high-fat diet; HMVECs: human microvascular endothelial cells; IFNG: interferon gamma; IL6: interleukin 6; MTS: Masson's trichrome staining; NFD: normal-fat diet; siRNA: small interfering RNA; SMAD3: SMAD family member 3; TGFB: transforming growth factor β; TNF: tumor necrosis factor; VEGFA: vascular endothelial growth factor A.

Dataset Information

Endothelial Cell-Specific Molecule 1 Promotes Endothelial to Mesenchymal Transition in Renal Fibrosis.

Publications

Endothelial Cell-Specific Molecule 1 Promotes Endothelial to Mesenchymal Transition in Renal Fibrosis.

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