ニューラミニダーゼ1活性が、ヘテロ接合性不全マウスにおける腎臓によるバソプレシン受容体を介した水分および電解質保持の増強に寄与する。

UNLABELLED: 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 ( ). Accumulating evidence suggests renal dysfunction, including enhanced sodium and water retention as an underlying cause of blood pressure elevation resulting from heterozygous deletion of ( ) 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 haploinsufficiency. Adult male and female and 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 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 but not mice, while both sexes of 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 mice. NEU1 blockade strikingly enhanced the natriuretic effect of furosemide and amiloride in male and modestly in mice. Taken together, we conclude that 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 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; , 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.