Podocyte Microenvironment in Diabetic Nephropathy

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): The current proposal is critical for the development of an academic career for the PI in diabetes nephropathy research. The PI feels that if afforded the opportunity to achieve his immediate career goals; to refine the skills, to acquire knowledge and to facilitate learning new methodologies necessary to conduct this research study, he will be prepared to accomplish his long-term goal of developing into independent investigator with expertise in DN complications. The PI has made significant contributions to the field of diabetic kidney disease and is now poised to begin transitioning toward an independent career. Diabetes mellitus is the leading cause of end stage renal disease with markedly higher morbidity and mortality rates. Diabetes and diabetic nephropathy (DN) is a disorder of the immune system. Infiltration of the diseased kidneys by inflammatory cells such as monocytes/macrophages supports the role of inflammation as an etiological factor. In DN, alterations in the podocyte niche (microenvironment) are likely responsible for abnormal podocyte function leading to progressive albuminuria and progressive renal failure. Podocyte function is intimately linked to its complex cytoskeletal structure. As a result of injury, cytoskeletal rearrangement ensues leading to foot process effacement. We hypothesize that macrophages contribute to direct podocyte injury and/or abnormal podocyte niche leading to DN and that adenosine A2A-agonist reverses this process and attenuates injury. Aim 1 tests the hypothesis that kidney macrophage recruitment directly contributes to diabetic renal injury. Aim 2 tests the hypothesis that macrophages directly mediate podocyte injury and/or create an abnormal podocyte niche leading to podocyte injury. Aim 3 tests the hypothesis that A2A-agonists ameliorate renal injury associated with DN by regulating macrophages/podocyte interaction and/or by directly affecting podocyte function. An understanding of the interaction between diabetes, macrophages and podocytes may help to better elucidate the mechanisms involved in diabetic renal disease and lead to the development of new therapeutic strategies to manage this disease process.