Effects of Elastin Haploinsufficiency and NEU-1 Blockade on Vasopressin-mediated Sodium and Water Handling by the Kidney

The elastin receptor complex (ERC), composed of NEU-1, protective protein/cathepsin A, and elastin-binding protein, is activated by bioactive peptides generated from elastin protein processing in the extracellular matrix (ECM), thereby regulating cellular functions essential for physiologic homeostasis. Previous studies have established that elastin haploinsufficiency (Eln+/–) accelerates ECM remodeling and increases elastin protein fragmentation, a process linked to arteriopathy, hypertension, and kidney dysfunction. However, whether abnormal ERC activity resulting from Eln haploinsufficiency directly contributes to renal dysfunction and hypertension remains unknown. We hypothesized that renal dysfunction due to Eln haploinsufficiency is mediated by enhanced renal sodium and water reabsorption driven by increased ERC activity in renal tubules. We further elucidated the mechanistic role of ERC in modulating vasopressin-dependent sodium and water handling regarding sex-dependent differences. To test this, we measured urine flow and sodium excretion rates in adult male and female wild-type (WT) and Eln+/- mice subjected to acute volume loading (6% of body weight) with 5% dextrose in saline, and administered pharmacological interventions targeting vasopressin V2 receptor (V2R) activity (tolvaptan for blockade, desmopressin for stimulation), ERC inhibition (2,3-didehydro-2-deoxy-N-acetylneuraminic acid, DANA), ENaC, and NKCC2 (amiloride and furosemide, respectively). In male WT mice, V2R blockade with tolvaptan (1, 2, and 3 mg/kg, i.p.) induced a dose-dependent increase in urine flow rate without affecting sodium excretion, while Eln+/- male mice showed no response. V2R stimulation with desmopressin (0.02, 0.06, and 0.2 mg/kg, i.p.) markedly increased urine sodium excretion in WT mice but not in Eln+/- mice, and both sexes of Eln+/- mice exhibited enhanced suppression of urine flow rate. ERC inhibition with DANA (10 mg/kg, i.p.) produced a modest increase in urine sodium excretion in male mice of both genotypes, but augmented urine flow rate only in male WT mice; notably, DANA potentiated the natriuretic effect of furosemide (10 mg/kg, i.p.) in male WT but not Eln+/- mice. Taken together, we conclude that Eln haploinsufficiency disrupts vasopressin-dependent sodium and water reabsorption by sex-dependently altering ERC-mediated modulation of NKCC2. These findings reveal a novel mechanism by which abnormal ERC activity contributes to renal dysfunction and hypertension and highlights the potential of ERC as a therapeutic target in hypertensive kidney disease. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.