Diabetologie und Stoffwechsel 2016; 11 - FV22
DOI: 10.1055/s-0036-1580769

Protective function of ELMO1 in renal development under diabetic conditions within zebrafish and in human diabetic nephropathy

K Sharma 1, K Heckler 1, S Stoll 1, JL Hillebrands 2, K Kynast 3, E Herpel 3, S Porubsky 4, PP Nawroth 5, J Kroll 1
  • 1Vascular Biology, Mannheim, Germany
  • 2Department of Pathology and Medical Biology, Groningen, Netherlands
  • 3Pathology, Heidelberg, Germany
  • 4Pathology, Mannheim, Germany
  • 5Medicine I and Clinical Chemistry, Heidelberg, Germany

Background and aims: Engulfment and cell motility 1 (ELMO1) protein functions as a guanine exchange factor for Rac1 and protects endothelial cells from apoptosis. GWAS data suggests that polymorphisms in different regions of human ELMO1 acts as a contributing factor for the development of diabetic nephropathy (DN). Thus, this study aimed to identify the role played by ELMO1 in renal development in zebrafish, under diabetic conditions, and DN patients.

Materials and methods: ELMO1 expression in Wt1B:GFP zebrafish (GFP positive renal system) was knocked out using the CRISPR/Cas9 technology. Zebrafish were rendered diabetic via the knockdown of the insulin promoting factor, Pdx1, and nephron functional assays were carried out with TexasRed labelled Dextran to observe leakage via the pronephron. TUNEL assay was used to determine apoptosis and human kidney sections from controls and DN patients were stained to compare ELMO1 expression.

Results: It was observed that a knockout of ELMO1 within zebrafish embryos leads to pathophysiological changes within the pronephron, adversely affecting pronephric structure and appropriate ultrafilteration. Subsequently, renal structure and function is restored in diabetic zebrafish embryos upon over-expression of ELMO1. Zebrafish embryos upon loss of ELMO1 showed a significant increase of apoptosis within the pronephron, which consequently lead to the renal pathophysiological effects. Lastly, expression of ELMO1 within kidney samples of human patients was not significantly increased as compared to control samples.

Conclusion: Collectively, the results indicate that ELMO1 is extremely important for glomerular protection and renal cell survival via decreasing apoptosis, especially within the diabetic diseased renal conditions.