Pathophysiology and genetics of salt-sensitive hypertension

Abstract

Most hypertensive cases are primary and heavily associated with modifiable risk factors like salt intake. Evidence suggests that even small reductions in salt consumption reduce blood pressure in all age groups. In that regard, the ACC/AHA described a distinct set of individuals who exhibit salt-sensitivity, regardless of their hypertensive status. Data has shown that salt-sensitivity is an independent risk factor for cardiovascular events and mortality. However, despite extensive research, the pathogenesis of salt-sensitive hypertension is still unclear and tremendously challenged by its multifactorial etiology, complicated genetic influences, and the unavailability of a diagnostic tool. So far, the important roles of the renin-angiotensin-aldosterone system, sympathetic nervous system, and immune system in the pathogenesis of salt-sensitive hypertension have been studied. In the first part of this review, we focus on how the systems mentioned above are aberrantly regulated in salt-sensitive hypertension. We follow this with an emphasis on genetic variants in those systems that are associated with and/or increase predisposition to salt-sensitivity in humans.

Hypertensive heart disease: risk factors, complications and mechanisms

“…Salt sensitivity of blood pressure (SSBP) results in part from genetic polymorphisms in genes regulating sodium handling and those not related to sodium handling such as the Protein Kinase CGMP-Dependent 1 (PRKG1), cytochrome b-245 alpha (CYBA) chain (also known as p22-phox), branched chain amino acid transaminase 1 (BCAT1), Solute Carrier Family 8 Member A1 (SLC8A1), SLC4A5, Angiotensin II Receptor Type 1 (AGTR1), Selectin E (SELE), cytochrome P450 family 4 subfamily A member 11 (CYP4A11), Neuronal precursor cell expressed developmentally down-regulated 4-like (NEDD4l) and Visinin Like 1 (VSNL1) ( 129 – 133 ). As explained above, RAAS activation leads to vasoconstriction, increased systemic vascular resistance (SVR) and elevation in blood pressure ( 134 ). In individuals with SSBP, RAAS is altered in that renin stimulation is reduced in salt depletion and the mechanisms are not adequate to suppress renin in high salt intake hence worsening the adverse effects of salt on blood pressure ( 135 – 138 ).…”

“…The NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome is an oligomeric complex containing the NOD-like receptor NLRP3, the adaptor Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and caspase-1 implicated in salt sensitive hypertension ( 166 ). The inflammasome is activated when NF- κ B upregulates the inflammasome components and pro-IL-1β leading to the assembly of components to form the NLRP3 inflammasome signaling complex ( 134 , 166 ) ( Figure 5 ). Activation of the NLRP3 inflammasome leads to the release of pro-inflammatory cytokines IL-1β and IL-18 via pyroptosis that involves the cleavage of gasdermin D and development of pores in the membrane of cells through which the cytokines and other cellular contents are released ( 134 , 166 ).…”

“…The inflammasome is activated when NF- κ B upregulates the inflammasome components and pro-IL-1β leading to the assembly of components to form the NLRP3 inflammasome signaling complex ( 134 , 166 ) ( Figure 5 ). Activation of the NLRP3 inflammasome leads to the release of pro-inflammatory cytokines IL-1β and IL-18 via pyroptosis that involves the cleavage of gasdermin D and development of pores in the membrane of cells through which the cytokines and other cellular contents are released ( 134 , 166 ). It has been demonstrated that the NLRP3 inflammasome can be activated in high salt environments in an ENaC-dependent manner leading to IsoLG-protein adduct formation in dendritic cells and macrophages and antigen presentation to activate cells of the adaptive immune system and leading to hypertension as explained above ( 167 ).…”

Editorial: Inflammation in hypertensive disorders

“…The migration of T cells from lymphoid organs to the circulation depends on the interaction between the chemoattractant sphingosine-1-phosphate (S1P) and sphingosine-1-phosphate receptors one and 2 (S1PR1+2). FTY720 is a functional agonist of S1PR1 that prevents the egression of lymphocytes from secondary lymphoid organs to the circulation (Matloubian et al, 2004;Garris et al, 2014;Itani et al, 2022).…”

“…In recent years the pivotal role of the immune system in the development of hypertensive disorders has been increasingly recognized ( Harrison et al, 2011 ; Mattson, 2014 ; Madhur et al, 2021 ; Ertuglu and Kirabo, 2022 ). Renal immune cells are a common feature of both experimental and clinical hypertension ( Hughson et al, 2008 ; Crowley et al, 2010 ; De Miguel et al, 2011 ; Xiao et al, 2015 ; Evans et al, 2017 ; Banek et al, 2019 ; Maaliki et al, 2022 ). Lymphocytes and macrophages migrate to regions of injury in the kidney, and immunosuppression, whether pharmacologically or genetically induced, reduces blood pressure in preclinical models ( Guzik et al, 2007 ; Boesen et al, 2010 ; Crowley et al, 2010 ; Madhur et al, 2010 ; Mattson et al, 2013 ; Moes et al, 2018 ).…”