RAGE/Diaph1, Diabetes, and Kidney Disease: Mechanisms and Novel Therapeutic Strategies
Abstract
This application addresses the topic area of Diabetes. It is a well-established fact that diabetes is on the rise in the United States and throughout the world. Increases in consumption of calorie-rich but nutritionally unhealthy foods, combined with a more sedentary lifestyle with reduced physical activity, are critically associated with the increase in diabetes. For unclear reasons, compared to non-Veteran civilians, United States Veterans are affected by diabetes at a significantly higher rate. There are multiple complications of diabetes, and these cause significant loss of quality and duration of life in diabetic subjects. The incidence of kidney disease, which is a leading complication of diabetes, is 34% higher in the Veteran population versus non-Veteran subjects in the United States. The Veterans Health Association reports that 10.7% of Veterans have chronic kidney disease. Once set in motion, kidney disease in diabetes, or “diabetic nephropathy,” accelerates complications, most especially cardiovascular disease, which is a leading cause of heart attacks, strokes, and heart failure. The higher rates of these debilitating diseases in United States Veterans underscores the urgent need to identify the causes of these diseases and to identify new therapeutic approaches, as there is no cure for diabetic kidney disease. Our laboratory discovered a key molecule, called the receptor for advanced glycation endproducts, or RAGE, which multiple studies performed by us and others throughout the world have linked to the cause of diabetic kidney disease in animal models. Further, our colleague and co-investigator, Dr. Vivette D’Agati, a world-renowned kidney pathologist, has shown that RAGE and its partner molecule, DIAPH1, are highly expressed in human diabetic kidney, to greater degrees than that observed in the non-diabetic kidney, indicating that RAGE and DIAPH1 are at the “right place and the right time” to contribute to diabetic kidney disease. As with most tissues, the kidney is composed of multiple different types of cells, not all of which express RAGE and DIAPH1. Two specific cell types in the kidney, called podocytes and macrophages, which do express RAGE and DIAPH1, have been linked to the mechanisms that cause diabetic kidney disease. However, the specific connection between these two cell types, RAGE and DIAPH1 expression, and the cause of diabetic kidney disease, has yet to be established. Understanding if and how RAGE and DIAPH1 specifically contribute to the development of diabetic kidney disease is essential to both uncover mechanisms that cause this disease and to identify if blocking RAGE/DIAPH1 might be a new therapeutic strategy for diabetic kidney disease, for which there is no cure on the horizon. We have developed novel research tools to test the role of RAGE and DIAPH1 in diabetic kidney disease. First, we have generated new mouse models in which RAGE and DIAPH1 have been specifically modified, either in podocytes or in macrophages. By rendering these mice diabetic, we may study how the absence of RAGE or DIAPH1 in these two cell types affects the course of complications in the kidney. Second, we have developed novel drug like compounds that in test tube and animal testing, block the effects of RAGE and DIAPH1 actions in diabetic conditions. Given the very strong link between RAGE and DIAPH1 and diabetic kidney disease, the administration of these drug-like compounds to diabetic mice will offer the first test of concept that blocking RAGE actions may prevent or greatly delay the development of diabetic kidney disease. In our proposed work, we will use these entirely novel mice and drug-like compounds to dissect in great depth if and how RAGE and its partner DIAPH1 cause diabetic complications in the kidney. Since so little is known on exactly how the podocyte and the macrophage contribute to diabetic complications and so little is on the horizon for new therapies, our work holds
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710202
Entities
People
- Ravichandran Ramasamy
Organizations
- Grossman School of Medicine
- United States Army