Chronic Kidney Disease (CKD) is a major burden of public health affecting millions of people around the world. Even though many aspects of the complex mechanisms orchestrating progression of renal disease have been identified, so far there is no specific treatment to slow down or prevent CKD progression. Therefore, identifying novel specific therapeutic targets and proposing more effective treatments against the progression of CKD is one of the major challenges of public health today. Our preliminary data showed that genetic deletion of a protein named Celen (we can't disclose the real name in the general public because is under Inserm patent deposit), exacerbated the decline of renal function in the Ang II- and nephrotoxic serum (NTS)- induced models of CKD. Inversely, activation of Celen protects against oxidative stressors (enhanced at the early stage of CKD) and prevents increase of apoptotic markers in renal cells. The specific hypothesis behind this proposal, strongly backed-up by our preliminary data, is that activation of Celen will counteract the deleterious effects of chronic renal inflammation and fibrosis, and preserve renal structure and function during kidney diseases providing a novel therapeutic target against CKD. The objectives of the present proposal are to: 1) Evaluate the role of Celen in the progression of experimental kidney disease (NTS model) using cell-specific Celen (podocyte or endothelial) gene deletion. 2) Dissect the molecular pathways implicated in the signaling of Celen in the kidney and identify novel regulators in the progression of glomerulonephritis. Specifically, we will investigate the role of Celen in mitochondrial function (i.e mPTP opening, Ca2+ overload). Using RNA-Seq and ChIP-Seq/-qPCR technologies, we will identify the full range of Celen target genes and the epigenetic enzymes mediating its nuclear signaling. 3) Examine whether cell-specific overexpression of Celen (in podocytes or endothelial cells depending on the results of 1) in adult mice is sufficient to halt or reverse the progression of glomerulonephritis. 4) Determine if pharmacological activation of Celen is nephroprotective. 5) Explore the translational relevance of its expression in biopsies. Partner's 2 lab is in charge of a cohort (CORIRLA) of CKD patients at Tenon hospital, Paris. The proposed task is to explore the cellular localization of Celen and its downstream effectors in different types of glomerulonephritis. This is a pilot study. If the results are confirmed, they will pave the way for a wider study involving more patients and partners which will be the subject of a future financial demand. We have therefore assembled two groups of internationally distinguished investigators to continue an existing collaboration and conduct basic and translational kidney research. Both partners have complementary expertise: Partner 1 is a renowned expert of the signaling, pharmacology and disease mechanisms involving Celen and Partner 2 has an international recognized expertise in renal pathophysiology and experimental models of kidney disease along with platforms for renal hemodynamics and in vivo imaging. After 3 years, we expect to deliver the following results: 1) Establish Celen as a novel actor in CKD ; 2) Obtain an in-depth analysis of Celen signaling in nephroprotection ; 3) Demonstrate that pharmacological intervention on Celen slows down or arrests progression of CKD ; 4) Observational study of Celen expression and signaling pathways in selected human nephropathies. The impact of our proposal will be scientific by identifying a new pathophysiological mechanism of CKD, socioeconomic by providing a proof of concept of a new therapy approach for CKD and cultural by giving the opportunity to young fellows to receive a high quality training thus improving their capacity for further career development in the academic or private sector.