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Kidney Week

Abstract: PO1309

Vasopressin Induces Urinary Uromodulin Secretion by Activating Protein Kinase A

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Nanamatsu, Azuma, Tokyo Medical and Dental University, Tokyo, Japan
  • Mori, Takayasu, Tokyo Medical and Dental University, Tokyo, Japan
  • Ando, Fumiaki, Tokyo Medical and Dental University, Tokyo, Japan
  • Furusho, Taisuke, Tokyo Medical and Dental University, Tokyo, Japan
  • Mandai, Shintaro, Tokyo Medical and Dental University, Tokyo, Japan
  • Susa, Koichiro, Tokyo Medical and Dental University, Tokyo, Japan
  • Sohara, Eisei, Tokyo Medical and Dental University, Tokyo, Japan
  • Rai, Tatemitsu, Tokyo Medical and Dental University, Tokyo, Japan
  • Uchida, Shinichi, Tokyo Medical and Dental University, Tokyo, Japan
Background

Urinary uromodulin, secreted by renal tubular cells, protects against urinary tract infections (UTIs) and kidney stones. In contrast, the intracellular accumulation of uromodulin is associated with hypertension and chronic kidney disease (CKD). In addition, uromodulin gene mutations cause autosomal dominant tubulointerstitial kidney disease (ADTKD-UMOD) via abnormal intracellular accumulation of uromodulin. However, the physiological stimuli for urinary uromodulin secretion remain largely unknown.

Methods

We investigated the acute effect of vasopressin/cAMP signaling on urinary uromodulin secretion in mice and in kidney epithelial cells stably expressing uromodulin. Additionally, we assessed the effect of vasopressin/cAMP signaling in kidney epithelial cells stably expressing mutant uromodulin, which causes ADTKD-UMOD.

Results

Desmopressin, a vasopressin type 2 receptor agonist, dramatically increased short-term tubular uromodulin secretion in mice. Immunofluorescence studies and ultracentrifugation-based polymerization assay suggested that desmopressin induced intraluminal polymeric filaments of uromodulin, indicating physiologically functional secretion. As a result of increased excretion, uromodulin abundance in the murine kidney was clearly reduced by desmopressin. In the cellular model, apical uromodulin secretion was increased in response to vasopressin/cAMP signaling, consistent with in vivo experiments. We also demonstrated that the response was dependent on cyclic AMP-dependent protein kinase (PKA) signaling pathway. We further showed that cAMP signaling induced excretion of mutant uromodulin. cAMP signaling suppressed PERK phosphorylation, which was upregulated by mutant uromodulin, implying cytoprotective effects.

Conclusion

Our work revealed vasopressin/cAMP/PKA signaling as a physiological stimulus of urinary uromodulin secretion. This finding may provide the basis for novel treatment strategies for UTIs, kidney stones, and potentially hypertension, CKD and ADTKD-UMOD.

Funding

  • Commercial Support