Regulatory RNA in Hypertension and Renal Injury

PROJECT SUMMARY Hypertension is the No. 1 identifiable risk factor for disease burden and deaths worldwide. Endothelial dysfunction contributes to the development of hypertension. Once hypertension develops, kidney injury ensues in susceptible patients. Albuminuria and proteinuria are often modest in hypertension but are prominent in subgroups such as African American hypertensive patients and are predictors of unfavorable prognosis. microRNAs regulate target protein expression primarily by inducing mRNA degradation or translational repression. Like many regulatory mechanisms such as signaling pathways and transcriptional factors, microRNAs are potentially promiscuous but may achieve regulatory specificity in a defined cellular context, a notion that has been reinforced and validated with recent technological advancement. Several microRNAs have emerged as powerful regulators of cardiovascular and renal functions with strong relevance to human disease. miR-204 is one such “high value” microRNA. The most striking and intriguing finding of our study of miR-204 was an apparent dissociation of miR-204’s effects on hypertension and renal injury in mice treated with uninephrectomy, angiotensin II, and a high-salt diet. The Unx/AngII/salt model typically exhibits a sustained increase of mean arterial pressure of ~40 mmHg and develops renal injury including albuminuria. Global miR-204 gene KO (Mir204-/-) attenuated the development of hypertension in this model, reducing mean arterial pressure by up to 30 mmHg compared to wild-type mice. In contrast, renal injury in the Unx/AngII/salt model was exacerbated in Mir204-/- mice, showing several fold greater albuminuria. These striking findings suggest that the functional role of miR-204 might be broad and highly tissue-specific. We have generated seven (7) new strains of mice to examine tissue-specific roles of miR-204 and the underlying mechanisms. Based on strong preliminary data, we hypothesize that miR-204 in endothelial cells permits the full development of hypertension (Aim 1) while miR-204 in podocytes protects against the development of albuminuria in hypertension (Aim 2). In both aims, we will examine the pathophysiological role of miR-204 in specific cell types, investigate the role of specific target genes that have been nominated by RNA-seq and other analyses, and study cell type-specific regulation of mRNA translational activities. The proposed study will drive a new dimension of hypertension and tissue injury research where a gene or pathway acts in one cell type to promote hypertension and another cell type to attenuate renal injury. The study will elucidate novel and critically important aspects of the complexity of these diseases, promote tissue-targeted therapeutics, and advance the recently reinforced notion of cell type specificity of microRNA function.