Project I - Role of Bilirubin in Protection Against Cardiometabolic Syndrome in Obesity
Project II - Diabetes, Cerebral Vascular Dysfunction and Cognitive Impairments
Diabetes mellitus (DM) is one of the leading risk factors for cerebrovascular disease (CVD) and cognitive impairment, especially at the late stage with mild hypertension, but the underlying mechanisms have not been fully elucidated. Dementia is one of the major causes of disability, and the 5th leading cause of death in the elderly in the US. The annual cost for treating dementia is $159 billion, and is projected to rise to $511 billion by 2040. There is an urgent need to understand the mechanisms involved and for development of new therapeutic strategies to delay the onset and progression of these devastating diseases. Mounting evidence suggests that DM is associated with impaired endothelial function and neurovascular coupling, and elevated myogenic tone and reactivity at an early stage. The enhanced myogenic tone and activity in DM decline with age, however, it is to be determined whether CBF autoregulation is impaired in vivo and if it plays a role in the development of dementia in hypertensive DM. This proposal builds upon our preliminary data indicating that the myogenic response and CBF autoregulation are impaired in response to elevated cerebral perfusion pressure in our novel diabetic rat models. Following development of mild hypertension, DM rats exhibit BBB leakage, inflammation, vascular remodeling, neurodegeneration and cognitive dysfunction. Importantly, forced dilatation of middle cerebral artery (MCA) and CBF autoregulatory breakthrough occurring at lower pressure are only observed in older DM rats with long standing hyperglycemia and after they have developed mild hypertension. We also observed that the neurodegeneration is associated with elevated expression of beta amyloid (Aβ 1-42) and pTau (S416) in the brain in mild hypertensive DM rats, suggesting that Alzheimer-like neuronal cell death pathways are also activated. The enhanced expression of GFAP and IL-1β in hypertensive DM rats indicate that glial activation and inflammation may play a role in linking aging, diabetes and cognitive deficits. In translational studies, we found that cognitive impairment in elderly participants in a largely diabetic ARIC-NCS population may be associated with impaired CBF autoregulation. This proposal will use our novel non-obese types 1 and 2 DM rat models, which do not exhibit severe lipid and other metabolic derangements normally associated with DM, to investigate whether impaired myogenic response and CBF autoregulation contribute to cognitive impairment, and whether the synergistic effects of DM and hypertension promote development of cognitive deficits. We will also use luseogliflozin to normalize plasma glucose levels by inhibition of renal sodium-glucose co-transporter 2 (SGLT2) without altering blood pressure in our DM models, as we previously reported, to determine the role of hyperglycemia in cerebral vascular dysfunction and dementia. This proposal will address one of the significant gaps in this field by investigating whether chronic hyperglycemia, especially in association with hypertension, causes impairment of CBF autoregulation and dementia using our novel diabetic rat models.
Project III - Novel MRI Strategies to Assess Obesity-Induced Kidney Dysfunction and Improved Function after Bariatric Surgery
Early, pre-clinical renal injury is difficult to assess, particularly renal medullary injury and dysfunction. We will evaluate a comprehensive MR strategy to determine if surgical weight loss after bariatric surgery (vertical sleeve gastrectomy) improves subclinical renal medullary injury and dysfunction using several non-contrasted MR techniques including renal perfusion (arterial spin labeling and phase contrast MR), renal tissue oxygenation response to a furosemide stimulus (BOLD MR), and renal fibrosis (native T1 mapping). We will specifically evaluate if perirenal and renal sinus fat volumes (and subsequent reductions in volumes measured with MR) are associated with MR-derived measures of altered renal medullary function and renal fibrosis using these techniques. We will also assess whether reductions in specific fat depots after vertical sleeve gastrectomy are independently associated with improvement in measures of subclinical renal dysfunction beyond other traditional measures of adiposity. We will also determine relationships of perirenal and renal sinus fat (and subsequent reductions after bariatric surgery) and markers of sympathetic nervous activity, renin-angiotensin-aldosterone system activity and inflammation to provide further mechanistic insights into the link between perinephric fat and renal dysfunction. To achieve these aims, we will perform a comprehensive MR-imaging exam in 50 obese hypertensive and 50 obese non-hypertensive participants before and 1 and 2 years after vertical sleeve gastrectomy.