The goal of the current project is to investigate the role of microRNA miR-29 in the development of hypertension and renal injury and understand the mechanisms involved. MicroRNAs are endogenous, regulatory RNAs that primarily reduce protein expression by binding to the 3'-untranslated region (UTR) of target mRNAs. Numerous studies have demonstrated that microRNAs are powerful regulators of gene expression and play crucial roles in a wide range of disease processes including several cardiovascular and renal diseases. However, the functional role of most microRNAs in the development of systemic hypertension and hypertensive tissue injury remains unknown. The Dahl salt-sensitive (SS) rat is a widely used animal model of human hypertension and related renal injury especially in African Americans. The consomic SS.13BN rat exhibits significantly attenuated hypertension and renal injury and has been used as a control for studying disease mechanisms in the SS rat. We have reported that microRNA miR-29b is down-regulated in the kidneys of SS rats on a high-salt diet compared to SS.13BN rats. miR-29 directly suppresses at least 16 genes related to extracellular matrix (ECM) and helps to prevent interstitial fibrosis in SS.13BN kidneys. Moreover, we found in ongoing human studies that miR-29b was dysregulated in the kidneys of patients with hypertensive renal injury. However, it remains unknown whether the insufficiency of renal miR-29 contributes to the development of hypertension and renal injury in the SS rat, whether renal miR-29 protects SS.13BN rats from developing hypertension, what mechanisms mediate any effect of miR-29 on hypertension, and how the expression of miR-29 is regulated in the kidneys of SS rats. We hypothesize that miR-29 insufficiencies, specifically in the kidney, contribute to the development of salt-induced hypertension and renal injury.
In Aim 1, we will examine the functional role of miR-29 in the development of salt-induced hypertension and renal injury in the SS rat using tissue-specific miR-29 transgenic rats that we just developed and local knockdown of miR-29.
In Aim 2, we will examine mechanisms underlying the regulation of miR-29 and its protective effect using several approaches including a molecular complex pull-out and deep sequencing method that we just developed. Exciting preliminary data support the feasibility of the proposed project.

Public Health Relevance

Hypertension is a common abnormality that affects 29% of the adult population in the US. Hypertension is a major risk factor for a variety of severe diseases including end-stage renal disease. About 50% of hypertensive patients in the US do not have their blood pressure adequately controlled, and about 5 million patients are apparently resistant to current anti-hypertensive treatments. The proposed project could reveal novel molecular mechanisms of hypertension and drive forward the research on the role of non-protein- coding genes in hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL121233-01A1
Application #
8758397
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
OH, Youngsuk
Project Start
2014-07-17
Project End
2018-05-31
Budget Start
2014-07-17
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Medical College of Wisconsin
Department
Physiology
Type
Schools of Medicine
DUNS #
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
Wang, Feng; Zhang, Guangyuan; Lu, Zeyuan et al. (2015) Antithrombin III/SerpinC1 insufficiency exacerbates renal ischemia/reperfusion injury. Kidney Int 88:796-803

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