Aberrant Rac1–mineralocorticoid receptor pathways in salt‐sensitive hypertension

<jats:title>Summary</jats:title><jats:p> <jats:list> <jats:list-item><jats:p> According to Guyton's model, impaired renal sodium excretion plays a key role in the increased salt sensitivity of blood pressure (<jats:styled-content style="fixed-case">BP</jats:styled-content>). Several factors contribute to impaired renal sodium excretion, including the sympathetic nervous system, the renin–angiotensin system and aldosterone. Accumulating evidence suggests that abnormalities in aldosterone and its receptor (i.e. the mineralocorticoid receptor (<jats:styled-content style="fixed-case">MR</jats:styled-content>)) are involved in the development of salt‐sensitive (<jats:styled-content style="fixed-case">SS</jats:styled-content>) hypertension.</jats:p></jats:list-item> <jats:list-item><jats:p> Patients with metabolic syndrome often exhibit hyperaldosteronism and are susceptible to <jats:styled-content style="fixed-case">SS</jats:styled-content> hypertension. Aldosterone secretion from the adrenal glands is not suppressed in obese hypertensive rats fed a high‐salt diet because of the abundant production of adipocyte‐derived aldosterone‐releasing factors, which are independent of the negative feedback regulation of aldosterone secretion by the renin–angiotensin–aldosterone system. Increased plasma aldosterone levels lead to <jats:styled-content style="fixed-case">SS</jats:styled-content> hypertension via <jats:styled-content style="fixed-case">MR</jats:styled-content> activation in the kidney.</jats:p></jats:list-item> <jats:list-item><jats:p> Renal <jats:styled-content style="fixed-case">MR</jats:styled-content> activity is increased in Dahl salt‐sensitive rats fed a high‐salt diet, despite the appropriate suppression of plasma aldosterone levels. In this rat strain, activation of <jats:styled-content style="fixed-case">MR</jats:styled-content> in the distal nephron causes salt‐induced hypertension. This paradoxical response of the <jats:styled-content style="fixed-case">MR</jats:styled-content> to salt loading can be attributed to activation of Rac1, a small <jats:styled-content style="fixed-case">GTP</jats:styled-content>ase. In the presence of aldosterone, activated Rac1 synergistically and directly activates <jats:styled-content style="fixed-case">MR</jats:styled-content> in a ligand‐independent manner. Thus, Rac1 activation in the kidney determines the salt sensitivity of <jats:styled-content style="fixed-case">BP</jats:styled-content>. Together, the available evidence suggests that the aberrant Rac1–<jats:styled-content style="fixed-case">MR</jats:styled-content> pathway plays a key role in the development of <jats:styled-content style="fixed-case">SS</jats:styled-content> hypertension.</jats:p></jats:list-item> </jats:list> </jats:p>