Key result
In mice, Eln haploinsufficiency disrupts vasopressin-dependent modulation of sodium and water reabsorption by sex-dependently altering ERC-mediated modulation of NKCC2 and ENaC.
Why the study?
The pathophysiological mechanisms underlying enhanced renal sodium and water retention causing blood pressure elevation in Eln haploinsufficiency were poorly understood.
Eln haploinsufficiency disrupts vasopressin-dependent modulation of sodium and water reabsorption by altering ERC-mediated modulation of NKCC2 and ENaC, revealing a potential mechanism for hypertension in Williams syndrome.
Answers are grounded in this paper and cite their sources.
Hypothesis-generating for sex-specific vasopressin effects on renal sodium handling; leaves open human translation.
Elastin haploinsufficiency is a primary determinant of arteriopathy and hypertension that hallmark Williams syndrome (WS), a rare genetic disorder resulting from microdeletion of genes on human chromosome 7, including the elastin gene ( ELN ). Accumulating evidence suggests renal dysfunction, including enhanced sodium and water retention as an underlying cause of blood pressure elevation resulting from heterozygous deletion of Eln ( Eln +/- ) in mice that recapitulates the cardiovascular phenotype of WS. However, the underlying pathophysiological mechanisms are poorly understood. Here, we determined whether the activity of neuraminidase-1 (NEU1) of the elastin receptor complex (ERC) contributes to abnormal handling of water and electrolytes by the kidney in Eln haploinsufficiency. Adult male and female Eln +/+ and Eln +/- mice were subjected to acute extracellular fluid volume expansion with normal saline, combined with pharmacological intervention targeting vasopressin V2 receptor (V2R), NEU1, ENaC, and NKCC2. In male Eln +/+ mice, V2R blockade induced a dose-dependent increase in urine flow rate without affecting sodium excretion. Conversely, V2R stimulation with desmopressin markedly increased urinary sodium excretion in male Eln +/+ but not Eln +/- mice, while both sexes of Eln +/- mice exhibited marked suppression of urine flow rate. Abrogation of ERC signaling through NEU1 inhibition produced a modest increase in urinary sodium excretion in male mice of both genotypes but augmented urine flow rate only in male Eln +/+ mice. NEU1 blockade strikingly enhanced the natriuretic effect of furosemide and amiloride in male Eln +/+ and modestly in Eln +/- mice. Taken together, we conclude that Eln haploinsufficiency disrupts vasopressin-dependent modulation of sodium and water reabsorption by sex-dependently altering ERC-mediated modulation of NKCC2 and ENaC. These findings reveal a novel mechanism by which abnormal ERC activity due to Eln haploinsufficiency potentially contributes to renal dysfunction and hypertension. GRAPHICAL ABSTRACT AC, adenylyl cyclase; AQP2, aquaporin 2; CD, collecting duct; CNT, connecting tubule; DCT, distal convoluted tubule; EBP, elastin binding protein; Eln , elastin allele; ENaC, epithelial sodium channel; ERC, elastin receptor complex; Gs, stimulatory Gα subunit; NEU1, neuroaminidase1; NKCC2, sodium-potassium-chloride cotransporter; PPCA, protective protein/ cathepsin A; TAL, loop of Henle thick ascending limb; V2R, vasopressin receptor type 2
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Kaur et al. (2026) studied Elastin haploinsufficiency (Williams syndrome model). Pharmacological intervention targeting V2R, NEU1, ENaC, and NKCC2 vs. Eln +/+ (wild-type) mice was evaluated on Urine flow rate and urinary sodium excretion. In mice, Eln haploinsufficiency disrupts vasopressin-dependent modulation of sodium and water reabsorption by sex-dependently altering ERC-mediated modulation of NKCC2 and ENaC.
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