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Abstract: FR-PO508

WNK1 Is a Central Osmolality Sensor for Arginine Vasopressin Release and Acts Through OSR1/SPAK Kinase Cascade

Session Information

Category: Fluid, Electrolytes, and Acid-Base Disorders

  • 1101 Fluid, Electrolyte, and Acid-Base Disorders: Basic

Authors

  • Jin, Xin, University of Iowa Hospitals and Clinics, Iowa City, Iowa, United States
  • Xie, Jian, University of Iowa Hospitals and Clinics, Iowa City, Iowa, United States
  • Huang, Chou-Long, University of Iowa Hospitals and Clinics, Iowa City, Iowa, United States
Background

Terrestrial animals are subject to constant stress of water deprivation.
Maintaining internal osmolality constancy is essential for life. The circumventricular
organs (CVO’s) of brain including the organum vasculosum of the lamina terminalis
(OVLT) and subfornical organ (SFO) lack a blood-brain barrier. Neurons in OVLT and
SFO detect increases in serum osmolality that stimulates the production of
AVP in paraventricular nuclei (PVN) to be released in the posterior pituitary. We have recently reported that WNK1 in sensory neurons in CVOs functions as an osmolality sensor for AVP release (Xin et al., JCI, 2023). WNK1 activates Kv3.1 to increase action potential travelling down to PVN to increase AVP synthesis for release from the posterior pituitary. Here, we further investigated the hypothesis that OSR1/SPAK acts as the downstream kinase for WNK1 in regulating AVP release.

Methods

PVN nuclei from control mice and Spak-null mice with homozygous Osr1-floxed allele (Sapk-/-;Osr1flox/flox) were stereotaxically injected with Cre-recombinase-carrying retrograde AAV virus. Metabolic cage studies were performed in mice. Urine output, water intake, serum, urine osmolality, serum AVP and copeptin levels were measured.

Results

Increased osmolality either by water restriction or mannitol injection activated OSR/SPAK in OVLT as evident by increased serine-373 phospho-SPAK/ serine-325 phospho-OSR. Like Wnk1 deletion, double deletion of OSR/SPAK in OVLT caused polyuria with decreased urine osmolality that persisted in water restriction. Circulating levels of AVP and copeptin were increased by water restriction in control mice. In contrast, water restriction failed to increase the levels in OSR/SPAK-deletion mice. Knockdown of Kv3.1b channel in OVLT by shRNA reproduces the phenotypes.

Conclusion

WNK1 in osmosensory neurons in CVOs detects extracellular hypertonicity and mediates the increase in AVP release by activating Kv3.1 and increasing action potential firing from osmosensory neurons. OSR1/SPAK acts downstream of WNK1 to regulate AVP release. Our findings reveal that an intracellular protein acts as a sensor for extracellular tonicity and provide fresh insights into mechanism how body maintains osmolality constancy. Future studies will investigate how OSR1/SPAK regulates Kv3.1 channels.

Funding

  • NIDDK Support