Kidney and epigenetic mechanisms of salt-sensitive hypertension

Dietary salt intake increases blood pressure (BP) but the salt sensitivity of BP differs between individuals. The interplay of ageing, genetics and environmental factors, including malnutrition and stress, contributes to BP salt sensitivity. In adults, obesity is often associated with salt-sensitive hypertension. The children of women who experience malnutrition during pregnancy are at increased risk of developing obesity, diabetes and salt-sensitive hypertension as adults. Similarly, the offspring of mice that are fed a low-protein diet during pregnancy develop salt-sensitive hypertension in association with aberrant DNA methylation of the gene encoding type 1A angiotensin II receptor (AT_1AR) in the hypothalamus, leading to upregulation of hypothalamic AT_1AR and renal sympathetic overactivity. Ageing is also associated with salt-sensitive hypertension. In aged mice, promoter methylation leads to reduced kidney production of the anti-ageing factor Klotho and a decrease in circulating soluble Klotho. In the setting of Klotho deficiency, salt-induced activation of the vascular Wnt5a-RhoA pathway leads to ageing-associated salt-sensitive hypertension, potentially as a result of reduced renal blood flow and increased peripheral resistance. Thus, kidney mechanisms and aberrant DNA methylation of certain genes are involved in the development of salt-sensitive hypertension during fetal development and old age. Three distinct paradigms of epigenetic memory operate on different timescales in prenatal malnutrition, obesity and ageing.