Four-week inhibition of the renin-angiotensin system in spontaneously hypertensive rats results in persistently lower blood pressure with reduced kidney renin and changes in expression of relevant gene networks.

AIMS: Prevention of human hypertension is an important challenge and has been achieved in experimental models. Brief treatment with renin-angiotensin system (RAS) inhibitors permanently reduces the genetic hypertension of the spontaneously hypertensive rat (SHR). The kidney is involved in this fascinating phenomenon, but relevant changes in gene expression are unknown. METHODS AND RESULTS: In SHR, we studied the effect of treatment between 10 and 14 weeks of age with the angiotensin receptor blocker, losartan, or the angiotensin-converting enzyme inhibitor, perindopril [with controls for non-specific effects of lowering blood pressure (BP)], on differential RNA expression, DNA methylation, and renin immunolabelling in the kidney at 20 weeks of age. RNA sequencing revealed a six-fold increase in renin gene (Ren) expression during losartan treatment (P < 0.0001). Six weeks after losartan, arterial pressure remained lower (P = 0.006), yet kidney Ren showed reduced expression by 23% after losartan (P = 0.03) and by 43% after perindopril (P = 1.4 × 10-6) associated with increased DNA methylation (P = 0.04). Immunolabelling confirmed reduced cortical renin after earlier RAS blockade (P = 0.002). RNA sequencing identified differential expression of mRNAs, miRNAs, and lncRNAs with evidence of networking and co-regulation. These included 13 candidate genes (Grhl1, Ammecr1l, Hs6st1, Nfil3, Fam221a, Lmo4, Adamts1, Cish, Hif3a, Bcl6, Rad54l2, Adap1, Dok4), the miRNA miR-145-3p, and the lncRNA AC115371. Gene ontogeny analyses revealed that these networks were enriched with genes relevant to BP, RAS, and the kidneys. CONCLUSION: Early RAS inhibition in SHR resets genetic pathways and networks resulting in a legacy of reduced Ren expression and BP persisting for a minimum of 6 weeks.

Sympathetic Nervous System and Atherosclerosis.

Atherosclerosis is characterized by the narrowing of the arterial lumen due to subendothelial lipid accumulation, with hypercholesterolemia being a major risk factor. Despite the recent advances in effective lipid-lowering therapies, atherosclerosis remains the leading cause of mortality globally, highlighting the need for additional therapeutic strategies. Accumulating evidence suggests that the sympathetic nervous system plays an important role in atherosclerosis. In this article, we reviewed the sympathetic innervation in the vasculature, norepinephrine synthesis and metabolism, sympathetic activity measurement, and common signaling pathways of sympathetic activation. The focus of this paper was to review the effectiveness of pharmacological antagonists or agonists of adrenoceptors (α1, α2, ß1, ß2, and ß3) and renal denervation on atherosclerosis. All five types of adrenoceptors are present in arterial blood vessels. α1 blockers inhibit atherosclerosis but increase the risk of heart failure while α2 agonism may protect against atherosclerosis and newer generations of ß blockers and ß3 agonists are promising therapies against atherosclerosis; however, new randomized controlled trials are warranted to investigate the effectiveness of these therapies in atherosclerosis inhibition and cardiovascular risk reduction in the future. The role of renal denervation in atherosclerosis inhibition in humans is yet to be established.

Dexamethasone leads to Zn2+ accumulation and increased unbound Zn2+ in C2C12 muscle and 3T3-L1 adipose cells.

Skeletal muscle atrophy is associated with increases in circulating glucocorticoid levels and insulin resistance. Zinc accumulates in atrophic muscle, but the relationship between atrophy, insulin resistance, and Zn2+ homeostasis remains unclear. In this study, the effect of the glucocorticoid dexamethasone (DEX) on insulin and Zn2+ homeostasis was explored. Treatment of differentiated C2C12 skeletal myotubes and 3T3-L1 adipocytes with DEX significantly increased mRNA expression of the metal-binding proteins Mt1 and 2 and altered energy storage as shown by the increased size of lipid droplets in 3T3-L1 cells. In C2C12 cells the total cellular Zn2+ was higher after DEX treatment, and in both C2C12 and 3T3-L1 adipocytes, free unbound Zn2+ was increased. Insulin treatment led to a gradual increase in free Zn2+ in C2C12 cells, and no significant change in DEX-treated cells such that concentrations were similar 10 min after insulin treatment. These data demonstrate that DEX disturbs Zn2+ homeostasis in muscle and fat cells. Further study of the molecular pathways involved to identify novel therapeutic targets for treatment of skeletal muscle atrophy is warranted.

Telomere therapy for chronic kidney disease.

Chronic kidney disease (CKD) is estimated to affect almost 10% of individuals worldwide and is one of the leading causes of morbidity and mortality. Renal fibrosis, a central pathway in CKD progression (irrespective of etiology), is associated with shortened or dysfunctional telomeres in animal studies. Telomeres are specialized nucleoprotein structures located at the chromosome end that maintain genomic integrity. The mechanisms of associations between telomere length and CKD have not yet been fully elucidated, however, CKD patients with shorter telomere length may have decreased renal function and a higher mortality rate. A plethora of ongoing research has focused on possible therapeutic applications of telomeres with the overall goal to preserve telomere length as a therapy to treat CKD.

Chronic kidney disease or CKD is one of the leading causes of illness and death worldwide. Scarring of the kidney tissue that occurs in CKD has been associated with shorter telomeres in studies using rats. Telomeres, said to act as the cellular 'shoelace caps', maintain the structure of chromosomes, allowing for genetic material inside cells to divide correctly. The length of telomeres (TL) is influenced by diverse factors such as genetics and lifestyle. The underlying processes for the associations between TL and CKD are still not understood, however, patients with CKD and shorter TL have reduced kidney function and an increased death rate. Therefore, research is focused on possible ways to preserve TL and treat CKD.

Noncoding Genes on Sex Chromosomes and Their Function in Sex Determination, Dosage Compensation, Male Traits, and Diseases.

The mammalian Y chromosome has evolved in many species into a specialized chromosome that contributes to sex development among other male phenotypes. This function is well studied in terms of protein-coding genes. Less is known about the noncoding genome on the Y chromosome and its contribution to both sex development and other traits. Once considered junk genetic material, noncoding RNAs are now known to contribute to the regulation of gene expression and to play an important role in refining cellular functions. The prime examples are noncoding genes on the X chromosome, which mitigate the differential dosage of genes on sex chromosomes. Here, we discuss the evolution of noncoding RNAs on the Y chromosome and the emerging evidence of how micro, long, and circular noncoding RNAs transcribed from the Y chromosome contribute to sex differentiation. We briefly touch on emerging evidence that these noncoding RNAs also contribute to some other important clinical phenotypes in humans.

A Guide to the Short, Long and Circular RNAs in Hypertension and Cardiovascular Disease.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in adults in developed countries. CVD encompasses many diseased states, including hypertension, coronary artery disease and atherosclerosis. Studies in animal models and human studies have elucidated the contribution of many genetic factors, including non-coding RNAs. Non-coding RNAs are RNAs not translated into protein, involved in gene expression regulation post-transcriptionally and implicated in CVD. Of these, circular RNAs (circRNAs) and microRNAs are relevant. CircRNAs are created by the back-splicing of pre-messenger RNA and have been underexplored as contributors to CVD. These circRNAs may also act as biomarkers of human disease, as they can be extracted from whole blood, plasma, saliva and seminal fluid. CircRNAs have recently been implicated in various disease processes, including hypertension and other cardiovascular disease. This review article will explore the promising and emerging roles of circRNAs as potential biomarkers and therapeutic targets in CVD, in particular hypertension.