ELMO1 increases expression of extracellular matrix proteins and inhibits cell adhesion to ECMs

Abstract

We have previously identified the engulfment and cell motility 1 (ELMO1) as a susceptibility gene for diabetic nephropathy. To elucidate the role of ELMO1 in the pathogenesis of chronic renal injury, we examined the expression of Elmo1 in the kidney of a rat model for chronic glomerulonephritis (uninephrectomy plus anti-Thy1.1 antibody [E30] injection). We found that the expression of the Elmo1 was significantly increased in the renal cortex and glomeruli of uninephrectomized rats injected with E30 compared to controls. By in situ hybridization, the expression of Elmo1 was shown to be elevated in the diseased kidney, especially in glomerular epithelial cells. In COS cells, the overexpression of ELMO1 resulted in a substantial increase in fibronectin expression, whereas the depletion of the ELMO1 by small interfering RNA (siRNA) targeting ELMO1 significantly suppressed the fibronectin expression in ELMO1 overexpressing and control cells. We also found that the expression of integrin-linked kinase (ILK) was significantly increased in ELMO1 overexpressing cells, and the ELMO1-induced increase in fibronectin was partially, but significantly, inhibited by siRNA targeting ILK. Furthermore, we identified that the cell adhesion to ECMs was considerably inhibited in cells overexpressing ELMO1. These results suggest that the ELMO1 contributes to the development and progression of chronic glomerular injury through the dysregulation of ECM metabolism and the reduction in cell adhesive properties to ECMs.

DNA hypermethylation and DNA hypomethylation is present at different loci in chronic kidney disease

“…45,46 Decreased methylation was observed in the CKD case group relative to controls and blood-derived gene expression data suggests this may contribute to kidney damage by increasing ELMO1 expression potentially leading to abnormal regulation of the extracellular matrix. 47 This decrease in methylation was supported by a higher level of expression for the ELMO1 gene based on RNA-seq results. Increased ELMO1 production may also facilitate more interactions with COX2, thus promoting COX2 activity leading to extracellular matrix accumulation.…”

Review: Genetics of diabetic nephropathy

“…Subsequent in vitro functional analysis revealed that ELMO1 expression was elevated in cells cultured under high glucose conditions (25 mM) compared to cells cultured under normal glucose conditions (5.5 mM). Furthermore, we identified that the expression of extracellular matrix proteins such as type 1 collagen and fibronectin was increased in cells that overexpressed ELMO1, whereas the expression of matrix metalloproteinases (MMPs) was decreased [Shimazaki et al 2005[Shimazaki et al , 2006. Therefore, it is suggested that a constant excess of ELMO1 in subjects with disease susceptibility allele leads to the overaccumulation of extracellular matrix proteins and to the development and progression of diabetic glomerulosclerosis.…”

Genetic Factors in Diabetic Nephropathy

“…Maeda's group (50) in Japan subsequently demonstrated that ELMO1 expression was increased in an animal model of chronic glomerulonephritis, resulting in overexpression of extracellular matrix proteins and loss of cell adhesive properties; hence, ELMO1 could plausibly play a role in the development of several glomerular disorders, including DN.…”