More than 50% of hypertensive patients show an increased blood pressure sensitivity to salt intake. However, population-wide reduction of salt intake has proved to be difficult, making it ever more important to better understand the mechanism of salt-sensitive hypertension and provide a basis for developing new interventions. The kidney plays a key physiological role in the development of hypertension including salt- sensitive hypertension. Thousands of genes in the genome encode long non-coding RNAs (lncRNAs). lncRNAs can interact with and influence the function of other RNA or proteins. Few lncRNAs have been studied for their role in hypertension. Unlike most lncRNAs, MALAT1 (metastasis associated lung adenocarcinoma transcript 1; Malat1 in rodents) is conserved across many species and expressed at high abundance levels in several tissues including the kidney, which suggests MALAT1 might be important physiologically. However, MALAT1?s physiological and pathophysiological role remains largely unknown. We discovered recently that renal miR-214-3p targets and suppresses endothelial nitric oxide synthase (eNOS) directly, which contributes significantly to the development of salt-sensitive hypertension in rat models and possibly humans. This was supported by a systematic analysis of human sequence variants and all miRNA precursors, small RNA deep sequencing in human kidney biopsy specimens, kidney-specific inhibition of miR- 214-3p in Dahl SS rats, and a newly generated mutant rat strain. The Dahl SS rat is the model most widely used to study the molecular mechanism of human salt-sensitive hypertension. We have obtained a large series of preliminary data that suggest MALAT1 might be dysregulated in the kidneys of salt-sensitive humans and SS rats and might influence the development of salt-sensitive hypertension by regulating the renal miR-214-3p/eNOS pathway. We propose to investigate MALAT1?s role in the development of salt-sensitive hypertension (Aim 1), the role for the renal miR-214-3p/eNOS pathway in the effect of MALAT1 on hypertension (Aim 2), and the underlying molecular interactions (Aim 3). We will achieve these aims by using analysis of scarcely available human samples, combinatorial gene manipulation in animal models, and new methods including genome editing and RafTOP (rapid freezing with tagged oligonucleotide pullout). RafTOP is a method for identifying the native interactome for a specific RNA that we developed recently.
Hypertension is the No. 1 identifiable risk factor for deaths worldwide. The proposed study will explore the role of a member of a large, but poorly understood, group of genes (lncRNAs) in the development of salt- sensitive hypertension using human samples and model systems. The findings are expected to provide novel insights into the molecular mechanism underlying salt-sensitive hypertension and advance significantly the broad but underexplored area of regulatory genome research in hypertension.
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