The role of angiotensin-(1-7) in hypertension and hypertension-induced heart and kidney damage

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ABSTRACT Hypertension is a leading cause of death and originates in childhood. Hypertension in childhood is common, causes heart and kidney injury, and predicts adult hypertension, but poor treatment response occurs in 50% of children and increases the risk of heart and kidney injury. Predicting treatment response may improve health throughout one’s life, but no predictors currently exist. The reasons for poor treatment response and how children develop heart and kidney injury are not fully understood; these gaps limit patient care. Preliminary data suggest changes to angiotensin-(1-7), uric acid, and klotho may be critical to the early development of hypertension and organ injury. However, this has not been studied in pediatric hypertension. The goal of this K23 is to initiate a mentored research project and training plan to a) establish a foundation of clinical evidence of angiotensin-(1-7) in pediatric hypertension and b) obtain training, education, experience, and data needed to transition to an independent patient-oriented research career focused on addressing gaps between basic science and clinical research in the mechanisms of hypertension in order to prevent and treat cardiovascular disease across the lifespan. This prospective cohort study of children aged 5 to 17 years with hypertension will measure angiotensin-(1-7), uric acid, and klotho in blood and urine and use novel causal inference methods to analyze their relationships to blood pressure and measures of heart and kidney injury. The specific aims are: i) determine if angiotensin-(1-7) differs in hypertension subjects vs. normotensive controls and mediates effect of blood pressure lowering on heart and kidney injury in subjects; ii) evaluate if angiotensin-(1-7) predicts treatment response in subjects; and iii) determine if angiotensin-(1-7) mediates the relationships between uric acid and heart injury and klotho and kidney injury in subjects. The central hypotheses are that 1) angiotensin- (1-7) is lower in subjects vs. controls and mediates the effect of reduced blood pressure on improved outcomes in subjects; 2) angiotensin-(1-7) predicts treatment response in subjects; and 3) angiotensin-(1-7) mediates the associations of uric acid with heart injury and klotho with kidney injury in subjects. Results will lead to an improved understanding of pediatric hypertension by identifying differences in how the disease progresses in response to treatment and providing crucial evidence of how hypertension-related organ injury occurs. This will improve patient care by defining new types of disease and informing new treatment strategies. The Candidate is a tenure-track assistant professor with 75% protected time and research funds, equipment, and personnel supported by the department and institution. The Candidate has a well-defined mentored learning plan that provides training in large cohort studies, advanced statistics, assay and cellular mechanisms, and clinical cardiovascular measures. This K23 award will provide the resources necessary to support the Candidate’s transition to an independent research career in an area of growing public health importance.