Understanding Hypertension and Kidney Function from Whole Animal to the Genome
Current Research:Mitochondrial Genomic Expression and Development of Renal Neuroadrenergic Hypertension: The background work in our research group has evolved into understanding the relationships among expression of renal mitochondrial genes, inflammation, renal sympathetic nerve activity and the development of hypertension. This research began with the implementation of a rat breeding paradigm yielding a conplastic strain of offspring wherein the mitochondrial genome of spontaneously hypertensive rats (Aoki-Okamoto SHR) are concentrated on a background of solely nuclear genes from a normotensive Brown-Norway rat. We are now working to determine the specific mitochondrial genetic loci responsible for this model of hypertension. In these rats, with 98% normotensive Brown Norway nuclear genome and 100% hypertensive SHR mitochondrial genome, hypertension persisted in the majority of animals. Hypertensive animals had elevated renal and hypothalamic expression of AT1 receptors suggesting a direct linkage between mitochondrial gene expression, brain/kidney AT1 receptors and hypertension. Selective renal downregulation of 11 out of 13 mitochondrially expressed genes were seen in the hypertensive compared to normotensive animals. Reduced mitochondrial gene expression may lead to excess generation of reactive oxygen species and renal inflammation in both vascular and tubular structures (Collett et. al. PLoS One 10(8) 2015:e0136441.doi:10. 1371/journal.pone.0136441). These elevated ROS products lead to altered renal function and the elevation of blood pressure by as yet, undefined mechanisms.
Ongoing Major Research Projects: We have now moved into the translational model of spontaneously hypertensive African Green Monkeys (C. aethiops sabaeus) to explore the relationships between renal sympathetic nerve activity, inflammation and the generation of reactive oxygen species specifically within renal vascular and tubular structures. Our newly developed AGM colony (97% genome homology to H. sapiens) expresses spontaneous hypertension in over 35% of the individuals. We have published several recent abstracts demonstrating: 1) our ability to measure arterial pressure and heart by telemetry for over 3 months, 2) altered renal mitochondrial gene expression, 3) altered renal cortical adrenergic receptor expression and 4) significant left ventricular hypertrophy and altered renal glomerular morphology in the hypertensive individuals. This nonhuman primate with spontaneous hypertension and impending renal disease will not only yield new insights into the development of human essential hypertension but also provide the biomedical scientific community with a novel and necessary translational model for the long-term study of cardiovascular and end-stage renal disease.
University of Kentucky | Lexington, Kentucky| Tel: 859 253 3988