Senescence and Autophagy as Mediators of Glomerular Injury in Diabetes

Brigham And Women'S Hospital, Boston MA

Investigators

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Abstract

DESCRIPTION (provided by applicant): Diabetic Nephropathy is a highly prevalent and debilitating disease, which is characterized morphologically by degenerative changes of renal podocytes associated with a variable extent of foot process effacement, thickening of glomerular basement membranes, endothelial cell injury, and expansion of the mesangial matrix, all contributing to progressive renal failure. It has become clear in past years that podocytes are injured very early in the course of the disease, and studies on Diabetic Nephropathy have focused primarily on podocyte depletion as mediators of glomerular injury and proteinuria, either by detachment or by apoptosis. However, recent work by our group and others identified features of accelerated senescence in glomeruli of patients with Diabetic Nephropathy. Cellular senescence is an alternative cellular response to prolonged metabolic stress as seen in diabetes, and is characterized by irreversible cell cycle arrest. However, senescent cells remain metabolically active, and recent studies identified the Senescence-Associated Secretory Phenotype (SASP) as a novel means of intercellular communication. Autophagy is closely associated with the senescent phenotype, and is thought to serve as a regulator of both apoptosis and senescence. This project aims to define the role of senescence and autophagy in mediating glomerular injury in Diabetic Nephropathy, and to elucidate the potential role of the SASP in disease progression. To this end, the candidate aims to: 1) Study the role of hic-5 in promoting a senescent phenotype in podocytes in response to sustained diabetic stress through activation of an anchorage-dependent cell survival mechanism in vitro and in vivo, by use of cultured podocytes, mouse models of disease and subsequent validation of results in a collection of human kidney biopsies; 2) Establish the contribution of autophagy to promoting podocyte senescence in diabetic nephropathy in vitro and in vivo by use of cultured podocytes, mouse models of disease and subsequent validation of results in a collection of human kidney biopsies; and 3) Investigate the role of the Senescence Associated Secretory Phenotype in disease progression in the glomerulus by using the podocyte secretome as a platform to identify molecular mediators of glomerular injury, followed by validation using co-culture models. Understanding the role of senescence and its associated factors in promoting glomerular injury and intraglomerular cross talk in diabetic nephropathy and potentially other glomerular diseases may help to identify novel and specific therapeutic targets. PUBLIC HEALTH RELEVANCE: This project will help to elucidate mechanisms leading to chronic kidney disease in patients suffering from diabetes mellitus, which represents the leading cause of chronic kidney disease in the United States. About 20% to 30% of patients with diabetes develop diabetic nephropathy, and greater than 50% of all reported patients requiring dialysis or transplantation have diabetes. Consequently, the effects on our Medicare budget are immense: more than 10 billion dollars per year are spent on end stage renal disease patients with a primary diagnosis of diabetes mellitus, and we are currently still lacking specific therapies for prevention and early treatment of this devastating complication.