Lipocalin-2 and Mitochondrial dysfunction: role in Chronic Kidney Disease – LiMiT-CKD

Chronic Kidney Diseases (CKD) is a major public health concern that is estimated to impact between 10% and 15% of the world’s population and this number is expected to increase. CKD is characterized by a progressive decline in renal function can occur in response to a wide array of renal insults (diabetes, hypertension, ischemia or immune diseases). Once a critical number of nephrons has been lost, irreversible progression of CKD results in end-stage renal disease (ESRD). To date, therapeutic options to prevent CKD progression are limited. A key challenge for the development of preventive and therapeutic strategies is the understanding the molecular basis of CKD. By combining experimental CKD models with genomic and molecular approaches, our previous studies identified Lipocalin-2 (Lcn2) as a key mediator of CKD onset. However, the mechanisms by which Lcn2 drives renal parenchyma deterioration are unknown. We recently discovered that Lcn2 expression can regulate mitochondrial dynamics and function. It is of particular interest since mitochondrial dysfunction has been recently recognized as a contributing factor in CKD progression. Our proposal aims to characterize the molecular mechanisms by which Lcn2 regulates mitochondrial physiology. Using a combination of existing transgenic mouse models and surgical interventions, we will test whether the mitochondrial dysfunction induced by the expression of Lcn2 participates in the development of renal lesions that promote the progression of CKD. Finally, we propose to develop a therapeutic approach using Antisense-Oligonucleotides in order to abolish the expression of renal Lcn2 in order to halt the onset and progression of CKD. We expect this project to lead to the discovery of new therapeutic strategies likely to improve the care of patients with CKD.