Relationships among endogenous ouabain, α-adducin polymorphisms and renal sodium handling in primary hypertension

Abstract

Objective-The basolateral Na pump drives renotubular reabsorption. In cultured renal cells, mutant adducins, as well as sub-nanomolar ouabain concentrations, stimulate the Na-K pump.Methods-To determine whether these factors interact and affect Na handling and blood pressure (BP) in vivo, we studied 155 untreated hypertensive patients subdivided on the basis of their plasma endogenous ouabain or α-adducin genotype (ADD1 Gly460Trp-rs4961).Results-Under basal conditions, proximal tubular reabsorption and plasma Na were higher in patients with mutated Trp ADD1 or increased endogenous ouabain (P = 0.002 and 0.05, respectively). BPs were higher in the high plasma endogenous ouabain group (P = 0.001). Following volume loading, the increment in BP (7.73 vs. 4.81 mmHg) and the slopes of the relationship between BP and Na excretion were greater [0.017 ± 0.002 vs. 0.009 ± 0.003 mmHg/ (μEq min)] in ADD1 Trp vs. ADD1 Gly carriers (P < 0.05). BP changes were similar, whereas the slopes of the relationship between BP and Na excretion were lower [0.016 ± 0.003 vs. 0.008 ± 0.002 mmHg/(μEq min)] in patients with low vs. high endogenous ouabain (P < 0.05). In patients with high endogenous ouabain, volume loading increased the BP in the ADD1 Trp group but not in the Gly group (P < 0.05). Thus, patients with ADD1 Trp alleles are sensitive to salt and tubular Na reabsorption remains elevated after volume expansion.Conclusion-With saline loading, BP changes are similar in high and low endogenous ouabain patients, whereas tubular Na reabsorption increases in the high endogenous ouabain group. Saline loading unmasks differences in renal Na handling in patients with mutant adducin or high endogenous ouabain and exposes an interaction of endogenous ouabain and Trp alleles on BP.

Upregulation of Na+/Ca2+exchanger and TRPC6 contributes to abnormal Ca2+homeostasis in arterial smooth muscle cells from Milan hypertensive rats

“…In the MNS ϫ MHS F2 hybrid population, the mutation of the Add1 gene accounts for the 50% of the blood pressure (BP) difference between MHS and its normotensive counterpart (MNS) (9, 11). Adducin polymorphisms are linked with higher Na ϩ pump activity and enhanced constitutive tubular Na ϩ reabsorption in the kidney in both rats and humans (22,26,27,47,66). Sodium retention should cause a plasma volume expansion and an increased cardiac output (17,34).…”

cGMP-Dependent Protein Kinase 1 Polymorphisms Underlie Renal Sodium Handling Impairment

“…5 However, this protective mechanism is defective in clinical and experimental forms of hypertension. 3,4 Here, we show that, after an acute saline load on mild hypertensive patients, those carrying the risk PRKG1 GAT alleles presented a rightward shift of the PNat relationship compared with those carrying ACC. Thus, PRKG1 risk alleles seem to associate with a saltsensitive phenotype related to a loss of the inhibitory control of renal Na + reabsorption.…”

“…The slope of the PNat relationship between BP and Na + excretion (μEq/mm Hg per minute) was calculated for each patient by plotting Na + excretion on the y axis as a function of MBP on the x axis, observed both under basal conditions (T 0 ) and after 120 minutes of saline infusion (T 120 ), as previously reported. 4,7 MBP was calculated as one-third differential BP plus diastolic BP.…”

“…Any disturbance of these mechanisms, including gain-or loss-of-function mutations in single genes, may lead to hypertension. 3,4 Recently, intrarenal NO-cGMP has been indicated as a candidate mediator of PNat that occurs via activation of cGMP-dependent protein kinase 1 (PRKG1). 5 As shown in rats, PRKG1 promotes high BP-mediated natriuresis by inhibiting the basolateral α1 Na-K ATPase and the luminal Na-H exchanger type 3 (NHE3) localized in renal proximal tubuli.…”

“…In particular, salt-sensitive individuals respond to a high-salt diet with a large rise in BP, indicative of a blunted PNat relationship. 3,4 Several inter-related pathways involving tubular Na + and Cl − transports along the nephron are implicated in the maintenance of PNat. Any disturbance of these mechanisms, including gain-or loss-of-function mutations in single genes, may lead to hypertension.…”