Exploring the Role of ELMO1 in AKI

Background: Acute kidney injury (AKI) is a sudden episode of kidney failure linked to a wide range of health conditions. High mortality in AKI highlights the need to identify new therapeutic approaches. Recent studies revealed the association of ELMO1 gene polymorphisms with diabetic nephropathy and lowering Elmo1 expression was protective against severe disease. ELMO1 is a cytoplasmic protein that promotes cytoskeletal reorganization during apoptotic cell clearance and cell migration. We have previously shown that loss of ELMO1 in neutrophils reduces neutrophil recruitment in inflammatory arthritis, without affecting bacterial recruitment or killing. Since immune cell recruitment and renal cell death directly affect AKI outcomes, we examined the role of ELMO1 in mouse models of AKI. Methods: We subjected wild type and Elmo1–/– mice to two different models of AKI: 1. Renal ischemia-reperfusion (IRI), a model of traumatic or post-operative kidney injury and 2. Cisplatin-induced nephrotoxicity. Results: In the bilateral renal IRI model, Elmo1-/- mice reduced expression of the kidney injury marker NGAL and local and global levels of inflammatory cytokines IL-6 and TNFα, as well as a significant decrease in remodeling gene expression. ELMO1-deficient mice also showed a reduction in neutrophils (Ly6G+) and apoptotic cells in renal tissue. Surprisingly, Elmo1–/– mice subjected to cisplatin-induced AKI displayed accelerated loss of kidney function and trends toward increased kidney injury marker NGAL and histological damage. We also noted elevated levels of apoptotic cells (cleaved caspase-3 stained) in the kidneys of cisplatin-injected Elmo1–/– mice, indicating potential for ELMO1 function in clearance of dying cells during cisplatin nephrotoxicity. Conclusion: Collectively, our data suggest distinct roles of ELMO1 in acute kidney injury induced by different damage trigger. Our ongoing studies are focused on cells involved in the phagocytosis of apoptotic cells (efferocytosis), having shown that the efferocytosis capacity of macrophages and renal tubular epithelial cells (RTEC) is not altered by loss of ELMO1. Our hypothesis is that ELMO1 could represent an attractive therapeutic target in ischemic injury, while potentially detrimental in the context of chemotherapy. Funding: Other NIH Support - NIAID