RAGE/DIAPH1, Diabetes, and Kidney Disease: Mechanisms and Novel Therapeutic Strategies
Abstract
Objectives and Rationale: All forms of diabetes carry a high risk of kidney complications because high levels of blood sugar damage the kidney. The epidemic of the most common form of diabetes, type 2 diabetes (T2D), is fueled by the steady rise in obesity; both conditions affect U.S. Veterans to a greater extent than non-Veterans. Chronic kidney disease (CKD) significantly increases the risk of reduced life span in affected persons. Diabetes and CKD are often found side-by-side. In diabetes and CKD, the leading causes of death are cardiovascular disease: heart attacks, strokes, and heart failure. Diabetes and CKD are particularly devastating for U.S. Veterans. The occurrence of CKD is approximately 34% higher in Veterans compared to non-Veterans. Recently, the Department of Veterans Affairs and the American Kidney Foundation announced a partnership to combat CKD (diabetes and hypertension are leading causes). CKD rises by 6% per year in Veterans. In 2018, CKD was evident in 31.6% of Veterans prior to diagnosis of diabetes. Nearly one in four Veterans receiving medical care from the Veterans Health Administration has diabetes. The Health and Retirement study suggested that among individuals older than age 50 years in the U.S., Veterans are at a higher risk of heart disease over the span of 20 years. Thus, the discovery of novel therapies for the complications of diabetes in the kidney and in the heart are essential to improve Veterans’ health. Our Expansion Award studies spring from the discoveries of the Investigator-Initiated Research Award in two major areas: First, we discovered that the expression of the receptor for advanced glycation end products (RAGE) and its cellular partner called DIAPH1, play key roles in diabetic kidney disease (DKD) in mice. The kidney is a very complex organ, composed of many cell types; each of these cell types plays roles in DKD. Our Investigator-Initiated Research Award uncovered the unexpected but highly significant finding that the effects of RAGE-DIAPH1 in diabetic kidney are due, at least in part, to white blood cells or inflammatory cells, that enter into the kidney from the bloodstream and then reside in the kidney. Once inside the kidney, these cells damage native kidney cells, leading to DKD. The Expansion Award will identify these mechanisms. Second, in our Investigator-Initiated Research Award, we showed that our novel small molecule antagonist of RAGE and DIAPH1, called RAGE229, offers protection in DKD in mice. Recently, a new class of drugs called SGLT 2 inhibitors has been approved for kidney and heart complications in diabetes, but these drugs are not cures: (1) they are not fully protective; (2) they have side effects, which limit application for all persons; and (3) they may not be safe for persons with insulin-dependent diabetes. Relationship of the Expansion Award application to the Investigator-Initiated Research Award: Our earlier studies directly led to the innovative studies proposed in the Expansion Award. First, regarding discovery 1 immediately above, the means by which inflammatory cells, through RAGE and DIAPH1, cause kidney damage in diabetes is not known. This is the work of the proposed Expansion Award. Knowledge to be gained will (1) uncover the mechanisms of inflammation in DKD, thereby revealing new therapeutic targets; and (2) identify molecules in the blood/urine that we can measure to track the state of DKD and the effectiveness of therapies. Second, regarding discovery 2 above, we propose that combining the SGLT2 inhibitors with RAGE229 may be more effective together than either agent alone. This is the work proposed in the Expansion Award. We will test if treatment of diabetic mice with SGLT2 inhibitors and RAGE229 affords greater benefit than either agent alone. Dr. Ramasamy (Partnering Principal Investigator) will expand these studies to look also at the diabetic heart. FY21 PRMRP Topic Areas and Areas of Encouragement: From our
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210302
Entities
People
- Ann Marie Schmidt
Organizations
- Grossman School of Medicine
- United States Army