Inverse Salt Sensitivity of Blood Pressure Is Associated with an Increased Renin-Angiotensin System Activity

Abstract

High and low sodium diets are associated with increased blood pressure and cardiovascular morbidity and mortality. The paradoxical response of elevated BP in low salt diets, aka inverse salt sensitivity (ISS), is an understudied vulnerable 11% of the adult population with yet undiscovered etiology. A linear relationship between the number of single nucleotide polymorphisms (SNPs) in the dopamine D2 receptor (DRD2, rs6276 and 6277), and the sodium myo-inositol cotransporter 2 (SLC5A11, rs11074656), as well as decreased expression of these two genes in urine-derived renal proximal tubule cells (uRPTCs) isolated from clinical study participants suggest involvement of these cells in ISS. Insight into this newly discovered paradoxical response to sodium is found by incubating cells in low sodium (LS) conditions that unveil cell physiologic differences that are then reversed by mir-485-5p miRNA blocker transfection and bypassing the genetic defect by DRD2 re-expression. The renin-angiotensin system (RAS) is an important counter-regulatory mechanism to prevent hyponatremia under LS conditions. Oversensitive RAS under LS conditions could partially explain the increased mortality in ISS. Angiotensin-II (AngII, 10 nmol/L) increased sodium transport in uRPTCs to a greater extent in individuals with ISS than SR. Downstream signaling of AngII is verified by identifying lowered expression of nuclear factor erythroid 2-related factor 2 (NRF2), CCCTC-binding factor (CTCF), and manganese-dependent mitochondrial superoxide dismutase (SOD2) only in ISS-derived uRPTCs and not SR-derived uRPTCs when incubated in LS conditions. We conclude that DRD2 and SLC5A11 variants in ISS may cause an increased low sodium sensitivity to AngII and renal sodium reabsorption which can contribute to inverse salt-sensitive hypertension.

Inverse salt sensitivity in normotensive adults: role of demographic factors

“…This may be due to RAAS hormone production in adipocytes, stimulation of aldosterone release via adipokines, and reduced adiponectin, which normally inhibits renin secretion [42,43]. As discussed previously, higher RAAS hormone levels on a low sodium diet and larger changes in RAAS hormones from low sodium to high sodium have been identified as a possible mechanism of ISS [9,40,44]. Thus, a smaller reduction in RAAS hormone levels from low sodium to high sodium as seen in obesity may predispose individuals with obesity to salt sensitivity and not ISS.…”

Anti-Inflammatory Effects of Peripheral Dopamine

“…The presence of DRD2 rs6276/rs6277 decreases the renal proximal tubule plasma membrane expression of D2R and its affinity to a D 2 -like receptor antagonist. The decreased expression of D2R in cells expressing DRD2 rs6276 can be related to the increased binding of miR-485-5p miRNA to the rs6276 sequence that represses D2R expression [ 196 ].…”