Sodium-glucose cotransporter-2 in Traumatic Brain Injury

About This Grant

Objective: Traumatic brain injury (TBI) is a common cause of morbidity and mortality in the veteran population. In the United States, there are an estimated 5.3 million people living with a TBI-related disability. TBI commonly leads to neurocognitive deficits, however, other systemic effects have also been associated with TBI including renal injury and accelerated atherosclerosis. TBI may affect the kidneys by increasing renal sympathetic tone with alteration of renal blood flow and glomerular filtration, leading to changes in sodium and water balance. Sodium-glucose cotransporter-2 (SGLT-2) expression in the kidneys may mediate effects of TBI on renal function, sympathetic activity and acceleration of vascular disease. SGLT-2 inhibitors have been shown to be beneficial towards preventing adverse outcomes in patients with a broad spectrum of cardiovascular and renal diseases. The goal of this application is to determine whether SGLT-2 inhibition is sufficient to prevent TBI-induced acceleration of atherosclerosis, and to assess the mediating role of renal sympathetic activity towards adverse vascular effects of TBI. Research Plan: To explore the role of SGLT-2 towards accelerated vascular disease induced by TBI, mouse models of TBI will be used to determine the effects of SGLT-2 inhibition or deficiency on brain injury, renal sympathetic activity, endothelial function, and the development of atherosclerosis. Biomarkers and possible mediators will be measured through a combination of flow cytometry, ELISA’s, magnetic resonance imaging, endothelial function, histological vascular endpoints related to TBI, and single cell expression profiling. The role of renal sympathetic activity towards vascular endpoints related to TBI will also be assessed. Methods: The strategy to accomplish the objectives will be to use in vivo mouse models, ex vivo, and in vitro assays to explore mediators of inflammation and vascular disease associated with TBI. Aim 1 will determine effects of SGLT2 inhibition or deficiency on accelerated atherosclerosis, brain injury, renal function, and biomarkers induced by TBI in atherosclerotic-prone mice. Aim 2 will determine the effect of SGLT2 inhibition or deficiency on blood pressure, endothelial function, single cell expression profiles, and leukocyte-endothelial interactions following TBI in atherosclerotic-prone mice. Aim 3 will determine the combined effects of renal denervation and SGLT-2 inhibition on atherosclerosis, brain injury, and biomarkers following TBI in atherosclerotic-prone mice.