Chronic Systemic Hyponatremia Potentiates Aberrant Regenerative Patterning Through Dysregulation of Biogenic Amine-Driven Morphogenetic Signaling in Mice

Hyponatremia is the most prevalent systemic ionic imbalance encountered clinically. Once considered morphogenetically silent owing to presumed osmoadaptation by peripheral tissues, emerging data suggest that chronic hyponatremia (CHN) can provoke reproducible defects in tissue repair. Nevertheless, the precise regenerative phenotypes elicited by CHN, the underlying molecular cues, and the reversibility of these abnormalities remain poorly defined. Here, we investigated whether biogenic amine–dependent morphogenetic signaling is linked to the CHN-induced impairment of innate regenerative patterning in a murine model of chronic syndrome of inappropriate antidiuresis. Using transgenic mice that constitutively overproduce a vasopressin-like peptide and exhibit persistent hyponatremia, we observed that sustained reductions in extracellular Na+ markedly delayed ear-punch closure and digit tip regrowth, two assays of innate appendage regeneration. Histological analysis revealed disorganized blastema architecture and diminished mesenchymal cell proliferation. Targeted metabolomics showed that serotonin and dopamine concentrations within the regenerating blastema were significantly lower in CHN animals than in iso-natremic littermates. Concomitantly, phosphorylation of extracellular signal-regulated kinase (ERK), a key effector of pro-regenerative signaling, was substantially reduced in the blastema of CHN mice. Remarkably, normalization of serum sodium restored orderly blastema formation, accelerated wound closure kinetics, replenished local serotonin and dopamine levels, and reinstated ERK phosphorylation to control values. These findings underscore the necessity of correcting hyponatremia in patients undergoing reparative therapies and highlight biogenic amine–ERK crosstalk as a tractable axis for enhancing regeneration under electrolyte-imbalanced conditions.