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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL121233-05A1
Application #
9970680
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
OH, Youngsuk
Project Start
2014-07-17
Project End
2024-01-31
Budget Start
2020-04-01
Budget End
2021-01-31
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Medical College of Wisconsin
Department
Physiology
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Liu, Yong; Usa, Kristie; Wang, Feng et al. (2018) MicroRNA-214-3p in the Kidney Contributes to the Development of Hypertension. J Am Soc Nephrol 29:2518-2528
Liang, Mingyu (2018) Epigenetic Mechanisms and Hypertension. Hypertension 72:1244-1254
Liu, Pengyuan; Liu, Yong; Liu, Han et al. (2018) Role of DNA De Novo (De)Methylation in the Kidney in Salt-Induced Hypertension. Hypertension 72:1160-1171
Chuppa, Sandra; Liang, Mingyu; Liu, Pengyuan et al. (2018) MicroRNA-21 regulates peroxisome proliferator-activated receptor alpha, a molecular mechanism of cardiac pathology in Cardiorenal Syndrome Type 4. Kidney Int 93:375-389
Widlansky, Michael E; Jensen, David M; Wang, Jingli et al. (2018) miR-29 contributes to normal endothelial function and can restore it in cardiometabolic disorders. EMBO Mol Med 10:
Kriegel, Alison J; Terhune, Scott S; Greene, Andrew S et al. (2018) Isomer-specific effect of microRNA miR-29b on nuclear morphology. J Biol Chem 293:14080-14088
Mattson, David L; Liang, Mingyu (2017) Hypertension: From GWAS to functional genomics-based precision medicine. Nat Rev Nephrol 13:195-196
Baker, Maria Angeles; Davis, Seth J; Liu, Pengyuan et al. (2017) Tissue-Specific MicroRNA Expression Patterns in Four Types of Kidney Disease. J Am Soc Nephrol 28:2985-2992
Huang, Baorui; Cheng, Yuan; Usa, Kristie et al. (2016) Renal Tumor Necrosis Factor ? Contributes to Hypertension in Dahl Salt-Sensitive Rats. Sci Rep 6:21960
Kriegel, Alison J; Baker, Maria Angeles; Liu, Yong et al. (2015) Endogenous microRNAs in human microvascular endothelial cells regulate mRNAs encoded by hypertension-related genes. Hypertension 66:793-9

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