High Elmo1 expression aggravates and low Elmo1 expression prevents diabetic nephropathy

Abstract

Human genome-wide association studies have demonstrated that polymorphisms in the engulfment and cell motility protein 1 gene (ELMO1) are strongly associated with susceptibility to diabetic nephropathy. However, proof of causation is lacking. To test whether modest changes in its expression alter the severity of the renal phenotype in diabetic mice, we have generated mice that are type 1 diabetic because they have the Ins2Akita gene, and also have genetically graded expression of Elmo1 in all tissues ranging in five steps from ∼30% to ∼200% normal. We here show that the Elmo1 hypermorphs have albuminuria, glomerulosclerosis, and changes in the ultrastructure of the glomerular basement membrane that increase in severity in parallel with the expression of Elmo 1. Progressive changes in renal mRNA expression of transforming growth factor β1 (TGFβ1), endothelin-1, and NAD(P)H oxidase 4 also occur in parallel with Elmo1, as do the plasma levels of cystatin C, lipid peroxides, and TGFβ1, and erythrocyte levels of reduced glutathione. In contrast, Akita type 1 diabetic mice with below-normal Elmo1 expression have reduced expression of these various factors and less severe diabetic complications. Remarkably, the reduced Elmo1 expression in the 30% hypomorphs almost abolishes the pathological features of diabetic nephropathy, although it does not affect the hyperglycemia caused by the Akita mutation. Thus, ELMO1 plays an important role in the development of type 1 diabetic nephropathy, and its inhibition could be a promising option for slowing or preventing progression of the condition to end-stage renal disease.reactive oxygen species | 3′-untranslated region | fibrosis

ELMO1 protects renal structure and ultrafiltration in kidney development and under diabetic conditions

“…We found that these patients, that we analysed, displayed an unaltered expression of ELMO1 within the renal parenchyma. This is in accordance with our research conducted on zebrafish embryos, but is in contrast to a recent published study which suggested that low ELMO1 expression prevents diabetic nephropathy development in mice23. It is common knowledge that no animal model completely adheres to the pathogenic mechanisms of human diabetic nephropathy.…”

The Susceptibility Genes in Diabetic Nephropathy

“…Functional studies have found that a high level of Elmo1 expression aggravated the progression of DN and vice versa. The severity of renal fibrosis, the amount of urinary albumin excretion and changes in the ultrastructure of the glomerular basement membrane in Akita diabetic mice paralleled the genetic levels of ELMO1 [50]. Possible mechanisms by which ELMO1 is involved in the pathogenesis of DN include: (1) ELMO1 and oxidative stress: ELMO1 promotes the production of reactive oxygen species by activating Rac and increasing the expression of NAD(P)H oxidase, thereby increasing oxidative stress in the kidney, leading to renal oxidative damage [50]; (2) ELMO1 and renal fibrosis: increased expression of ELMO1 promotes the expression of fibrogenic genes (such as TGF-β1 and genes encoding type 1 collagen and fibronectin, etc.)…”

“…The severity of renal fibrosis, the amount of urinary albumin excretion and changes in the ultrastructure of the glomerular basement membrane in Akita diabetic mice paralleled the genetic levels of ELMO1 [50]. Possible mechanisms by which ELMO1 is involved in the pathogenesis of DN include: (1) ELMO1 and oxidative stress: ELMO1 promotes the production of reactive oxygen species by activating Rac and increasing the expression of NAD(P)H oxidase, thereby increasing oxidative stress in the kidney, leading to renal oxidative damage [50]; (2) ELMO1 and renal fibrosis: increased expression of ELMO1 promotes the expression of fibrogenic genes (such as TGF-β1 and genes encoding type 1 collagen and fibronectin, etc.) and inhibits the expression of anti-fibrotic genes (such as matrix metalloproteinase genes), leading to excessive accumulation of extracellular matrix proteins and thickening of the glomerular basement membrane and consequently resulting in the initiation and progression of diabetic glomerulosclerosis [46].…”

Tristetraprolin as a Therapeutic Target in Inflammatory Disease

“…For example, removal of the ARE from the TNFα mRNA in mice resulted in a severe TNFα overproduction syndrome and inflammatory bowel disease [32]. Smithies and colleagues [33, 34] achieved various levels of expression of their mRNAs and proteins of interest by inserting either labile or stable regions into the 3’UTRs of their target genes. Deletion of an AU-rich region of the interferon gamma mRNA 3’UTR stabilized this transcript, and resulted in increased secretion of interferon in the mouse [35].…”