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Abstract: FR-PO622

WNK1 as a Central Osmosensor for Vasopressin Release and Water Homeostasis

Session Information

Category: Fluid and Electrolytes

  • 901 Fluid and Electrolytes: Basic

Authors

  • Kuppusamy, Maniselvan, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States
  • Xie, Jian, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States
  • Huang, Chou-Long, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States
Background

The brain circumventricular organs organum vasculosum lamina terminalis (OVLT) and subfornical organ (SFO) lack blood-brain barrier and function as sensors for systemic osmolality. Hyperosmolality activates neurons in OVLT and SFO, leads to vasopressin production in cell bodies of magnocellular neurons in the paraventricular and supraoptic nuclei of hypothalamus and release through axonal termini in the posterior pituitary. Previous work focused on cell membrane resident proteins such as mechanosensitive channels TRPV1 and V4 as candidates of osmosensors. Results of knockout animal studies yet are conflicting. Compared to membrane proteins by responding to stretch, intracellular proteins may be better positioned to sense cell water content in response to changes in extracellular osmoles. WNK kinases are activated by hyperosmolality. We investigated the role of WNK1 in central osmosensing.

Methods

Wnk1-floxed mice were bred with synapsin-Cre mice to generate neuronal-specific Wnk1-knockout (KO) mice.

Results

Under ad lib water and food intake, average daily urine output was higher in KO mice (n = 6) than in control mice (n = 8) (1.57 ± 0.17 ml vs 1.03 ± 0.15 ml, p < 0.05). Daily water intake was also higher in KO than in control (4.84 ± 0.25 ml vs 4.14 ± 0.21 ml, p < 0.05). Serum osmolality in KO mice trended higher but not statistically significantly different from control (314 ± 4 vs 307 ± 3 mOsm/kg, p = 0.18). Urine osmolality was lower in KO than in control mice. The pattern of serum and urine osmolality suggests that defects in vasopressin release or action (i.e., diabetes insipidus) rather than primary polydipsia or osmotic diuresis as the cause of polyuria. To further distinguish between these possibilities, mice were water-deprived for 24 hrs. Urine output remained elevated in KO than control mice under water deprivation (1.17 ± 0.13 ml vs 0.63 ± 0.08 ml, p < 0.05). Serum osmolality was increased and the difference between KO and control was amplified by water deprivation (329 ± 4 vs 312 ± 3 mOsm/kg, p < 0.01). To support the hypothesis of blunted vasopressin release in neuronal Wnk1-KO, work is ongoing to measure serum vasopressin and copeptin levels in KO & control mice.

Conclusion

Our results suggest that WNK1 protein may function as an intracellular osmosensor for regulating vasopressin release.

Funding

  • NIDDK Support