No abstract

Background: The gene FOXO3, encoding the transcription factor forkhead box O-3 (FoxO3), is one of only two for which genetic polymorphisms have exhibited consistent associations with longevity in diverse human populations. Objective: Here, we review the multitude of actions of FoxO3 that are relevant to health, and thus healthy ageing and longevity. Methods: The study involved a literature search for articles retrieved from PubMed using FoxO3 as keyword. Results: We review the molecular genetics of FOXO3 in longevity, then current knowledge of FoxO3 function relevant to ageing and lifespan. We describe how FoxOs are involved in energy metabolism, oxidative stress, proteostasis, apoptosis, cell cycle regulation, metabolic processes, immunity, inflammation and stem cell maintenance. The single FoxO in Hydra confers immortality to this fresh water polyp, but as more complex organisms evolved, this role has been usurped by the need for FoxO to control a broader range of specialized pathways across a wide spectrum of tissues assisted by the advent of as many as 4 FoxO subtypes in mammals. The major themes of FoxO3 are similar, but not identical, to other FoxOs and include regulation of cellular homeostasis, particularly of stem cells, and of inflammation, which is a common theme of age-related diseases. Other functions concern metabolism, cell cycle arrest, apoptosis, destruction of potentially damaging reactive oxygen species and proteostasis. Conclusions: The mechanism by which longevity-associated alleles of FOXO3 reduce age-related mortality is currently of great clinical interest. The prospect of optimizing FoxO3 activity in humans to increase lifespan and reduce age-related diseases represents an exciting avenue of clinical investigation. Research strategies directed at developing therapeutic agents that target FoxO3, its gene and proteins in the pathway(s) FoxO3 regulates should be encouraged and supported.

Abstract-The kidney has long been invoked in the etiology of essential hypertension. This could involve alterations in expression of specific genes and microRNAs (miRNAs). The aim of the present study was to identify, at the transcriptome-wide level, mRNAs and miRNAs that were differentially expressed between kidneys of 15 untreated hypertensive and 7 normotensive white male subjects of white European ancestry. By microarray technology we found 14 genes and 11 miRNAs that were differentially expressed in the medulla. We then selected and confirmed by real-time quantitative PCR expression differences for NR4A1, NR4A2, NR4A3, PER1, and SIK1 mRNAs and for the miRNAs hsa-miR-638 and hsa-let-7c. Luciferase reporter gene experiments in human kidney (HEK293) cells confirmed the predicted binding of hsa-let-7c to the 3Ј untranslated region of NR4A2 mRNA. In the renal cortex we found differential expression of 46 genes and 13 miRNAs. We then confirmed expression differences for AIFM1, AMBP, APOE, CD36, EFNB1, NDUFAF1, PRDX5, REN, RENBP, SLC13A1, STX4,. Functional experiments in HEK293 cells demonstrated that hsa-miR-663 can bind to the REN and APOE 3Ј untranslated regions and can regulate REN and APOE mRNA levels, whereas hsa-miR-181a regulated REN and AIFM1 mRNA. Our data demonstrated for the first time that miRNAs can regulate renin expression. The observed downregulation of 2 miRNAs in hypertension could explain the elevation in intrarenal renin mRNA. Renin, CD36, and other mRNAs, as well as miRNAs and associated pathways identified in the present study, provide novel insights into hypertension etiology. (Hypertension. 2011;58:1093-1098.) • Online Data SupplementKey Words: microarrays Ⅲ microRNAs Ⅲ renin angiotensin system Ⅲ kidney Ⅲ hypertension S olving the molecular etiology of essential hypertension has been challenging. 1 Studies of selected blood pressure (BP) genes and large genome-wide association studies have identified only a handful of gene variants of small effect sizes. The interplay between genetic and environmental factors that contributes to the heterogeneity of hypertension has made the identification of causative alleles, genes, and transcripts difficult. 1 A further impediment has been the difficulty in obtaining suitable human tissue samples other than blood.Guyton and colleagues 2,3 theorized that hypertension is caused by a primary defect in the kidney. This idea has gained support from rare monogenic forms of hypertension, in which single mutations in genes responsible for renal sodium reabsorption 4 result in BP elevation. 3 MicroRNAs (miRNAs) are important for physiological and pathophysiological processes in various diseases. 5 These 18 to 30 nucleotides noncoding RNAs regulate the expression and translation of half of protein-coding mRNAs in humans by binding to target sites in the 3Ј untranslated region (UTR) to destabilize them or impede translation. 5 If miRNAs modulate mRNAs for BP genes, they could form the basis for novel antihypertensive therapies. 6,7 Knowledge of effects of miRNAs ...