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

Tung-Wei Hung,Chu-Che Lee,Yong-Syuan Chen,Chao-Yang Chu,Li-Sung Hsu,Chen-Lin Yu,Yi-Hsien Hsieh,Jen-Pi Tsai

doi:10.3390/toxins12080506

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 α-smooth muscle actin (α-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, α-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.

Highlights

Chronic kidney disease (CKD), characterized by progressive renal dysfunction, is recognized as a major public health problem with high morbidity and mortality worldwide [1]
endothelial cell-specific molecule 1 (ESM1) in the progression of renal fibrosis, this study aims to determine whether ESM1 overexpression promotes renal fibrosis and endothelial-to-mesenchymal transition (EndoMT) pathways using in vitro mouse kidney cell culture and an in vivo mouse model of renal fibrosis induced by unilateral ureteral obstruction
Masson tissue staining revealed a time-dependent increase in blue-stained interstitial collagen fibers in the ureteral obstruction (UUO) group, but no such fibers in the sham surgery group (Figure 1E). These results suggest that ESM1 may be involved in renal fibrosis progression

Summary

Introduction

Chronic kidney disease (CKD), characterized by progressive renal dysfunction, is recognized as a major public health problem with high morbidity and mortality worldwide [1]. As ESM1 expression is high in inflamed endothelium, ESM1 is thought to play a role in the pathogenesis of vascular disorders, inflammation, and endothelial dysfunction [8]. Plasma ESM1 levels correlate with inflammation severity and poor survival in coronary artery disease [9], chronic kidney disease [10], IgA nephropathy [11], and sepsis [12]. Plasma and urinary ESM1 levels may serve as potential markers of microvascular inflammation and are elevated in patients with antibody-mediated rejection [15]. Recent studies have shown that injury to glomerular endothelial cells directly contributes to podocyte and mesangial cell damage and the development of glomerulosclerosis [16,17,18]

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