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.
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.