Glomerular Cell-Cell Crosstalk and Injury

Icahn School Of Medicine At Mount Sinai, New York NY

Investigators

Linked publications, trials & patents

Abstract

Project Summary Chronic kidney disease (CKD) is estimated to affect over 14% of US adults and is increasing in prevalence worldwide. The majority of cases are caused by glomerular diseases with sclerotic lesions, and transforming growth factor β expression in podocytes is a common stress response signal associated with segmental sclerosis. Using several experimental models of FSGS and DKD with proteinuria, we established a new hypothesis for “glomerular cell-cell crosstalk”, in which there is interdependence of the cells within the glomerular filtration barrier (GFB) for health and dysfunction. We showed that activation of podocytes results in TGFβ signaling followed by increased Edn1 receptor A (ETA)-mediated mitochondrial oxidative stress and dysfunction of adjacent glomerular endothelial cells (GEC), which, in response, release factor(s) that mediate damage and depletion of adjacent podocytes and albuminuria. Under the support of this award, we searched for these GEC-secreted cytotoxic factors that mediate podocyte injury and GFB breakdown. By dissecting the upstream and downstream mediators of pathogenesis in GEC stress and podocyte injury, we believe that we have made significant progress towards these goals including: 1) confirmed that a similar stressed GEC-to-podocyte crosstalk underlies segmental lesions in DKD; 2) confirmed the release of endothelin-1 by activation of TGFβ signaling in podocytes, and performed transcriptomic analysis of isolated GECs after activation of TGFβ in podocytes and identified novel early GEC responses, and phenotypic markers of cell crosstalk in vivo including changes in the glycocalyx and in extracellular matrix; 3) using state of the art proteomics we identified a panel of novel molecules released by stressed GECs that are pro-apoptotic to podocytes; 4) we discovered that the stressed GECs released molecules are released into the urine reflecting early GEC injury and a potential urine biomarker of disease progression; 5) we generated novel an endothelial cell conditional knockout mice; 6) finally, we have developed antisense oligonucleotides for blocking stressed GECs released molecules in mice with CKD as a novel therapeutic strategy. We hypothesize that the identified stress GEC-derived secreted factors mediate podocyte injury and loss in CKD, and that blocking these factors is a therapeutically viable strategy to prevent disease progression. In this competitive renewal application, we aim to test this hypothesis in the following 3 specific aims: SPECIFIC AIMS: 1) To determine the podocyte responses to stressed glomerular endothelial cells derived factors; 2) To dissect the impact of stressed glomerular endothelial cells derived factors on the GFB and inhibition with antisense oligonucleotides. 3) To evaluate novel antisense oligonucleotides against stressed glomerular endothelial cells derived factors and establish their efficacy for treatment for glomerular diseases in vivo. LONG-TERM: The studies proposed in this application will advance our understanding of communications between cells in the glomerulus that underlie the initiation and progression of glomerular disease. The outcomes will help identify novel diagnostic approaches and lay the foundation for novel treatments for CKD.