Preclinical studies on the preventive effects of neuregulin-1 in acute renal failure.

Acute kidney injury (AKI) is a frequent and deadly complication of numerous pathological disorders. In AKI, interactions between endothelial cells, tubular epithelial cells and inflammatory cells are disturbed leading to irreversible kidney damage. Although AKI is associated with a high mortality of up to 60%, there is still no therapy for this disease. This project is based on recent observations in the Laboratory of Physiopharmacology (UA) showing previously unknown protective effects of neuregulin-1 (NRG-1) on the kidney. NRG-1 is a member of the epidermal growth factor family and has well-characterized roles in the development of the nervous system and the heart. In 2015, we discovered that activation of the NRG-1/ErbB pathway using recombinant NRG-1 protects against contrast-induced AKI in mice. In the present proposal, we describe experiments to confirm these findings and to define the mechanisms involved in the protective effects of NRG-1 on AKI.The main purpose of this proposal is to confirm the protective effects of the NRG-1/ErbB pathway in AKI and to elucidate underlying mechanisms. In order to reach this aim, we will perform multiple 'gain and loss of function' experiments in transgenic mice with cell-specific deletion of ErbB4 in endothelial cells, tubular cells, and myeloid cells. Transgenic mice and wild type littermates will be submitted to various forms of AKI, radiocontrast-induced and ischemia/reperfusion induced AKI, in presence or absence of NRG-1. The readouts of AKI will be (i) glomerular filtration rate measurements with FITC-sinistrin clearance and creatinin levels; (ii) histological assays; and (iii) measurements of mRNA expression of inflammatory mediators. NRG-1 is currently being tested in clinical trials for heart failure; the present research will reveal the therapeutic potential of NRG-1 for treatment of acute kidney injury.

Keywords:TUBULAR NECROSIS, NEUREGULIN-1, KIDNEY DISEASE, INFLAMMATION

Disciplines:Physiology, Urology and nephrology