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Abstract: TH-PO337

The Long-Term Effect of Vasopressin on Transcriptome and DNA Accessibility in Cortical Collecting Duct

Session Information

Category: Fluid‚ Electrolyte‚ and Acid-Base Disorders

  • 1001 Fluid‚ Electrolyte‚ and Acid-Base Disorders: Basic


  • Kikuchi, Hiroaki, National Institutes of Health, Bethesda, Maryland, United States
  • Chen, Lihe, National Institutes of Health, Bethesda, Maryland, United States
  • Jung, Hyun Jun, Johns Hopkins University, Baltimore, Maryland, United States
  • Park, Euijung, National Institutes of Health, Bethesda, Maryland, United States
  • Knepper, Mark A., National Institutes of Health, Bethesda, Maryland, United States

Group or Team Name

  • Epithelial Systems Biology Laboratory, Systems Biology Center

Vasopressin binds to V2 receptors in collecting duct principal cells triggering protein kinase A (PKA) –dependent signaling and increased expression of the Aqp2 gene. Vasopressin signaling is important not only for Aqp2 transcription, but also for cyst genesis in autosomal dominant polycystic kidney disease (ADPKD), which is one of the world’s most common inherited life-threatening conditions. However, signaling pathways responsible for long-term vasopressin action in native renal collecting duct cells are incompletely understood.


Experiments were done in mice undergoing administration of vehicle (Veh) or vasopressin analog, desmopressin (dDAVP) by osmotic minipumps (2 ng/hour, 5days) without water restriction (n=4 mice for each group). Spot urine samples were collected on each day until day 5 and the urine osmolality was monitored. RNA-seq transcriptomics and ATAC-seq- based DNA accessibility assessment were carried out in microdissected cortical collecting ducts (CDs).


Spot urine osmolality was significantly increased by 5 day dDAVP treatment compared to Veh treatment (3063 ± 323, 2243 ±354 mosm/kg, respectively). Single tubule RNA-seq of CCDs showed that there were 485 genes that were increased (Padj less than 0.05 and log2 dDAVP/Veh greater than 0.50) and 2317 transcripts that were decreased (Padj less than 0.05 and log2 dDAVP/Veh less than -0.50) out of a total of 12,653 transcripts with TPM values greater than 1. Aqp2 mRNA abundance was increased by 140% in the cortical CD by dDAVP. Aqp3 was also significantly increased by 90 %. In contrast to dDAVP effects in cultured mpkCCD cells, cell cycle-related transcript such as Cdk1, E2f1 and Mki67 were highly upregulated by dDAVP (dDAVP:Veh ratio = 10.30, 5.76 and 5.03). Motif analysis (HOMER) of sequences corresponding to ATAC-seq peaks significantly upregulated by dDAVP, revealed binding site motifs corresponding to Ets-Family, Klf-Family and E2f-family transcription factors.


Long-term infusion of dDAVP is associated with gene expression changes consistent with cellular proliferative effects in native mouse CDs, which could be due to either a direct or an indirect action of dDAVP. Future studies will examine the molecular mechanisms involved and a possible connection to the role of V2 receptors in the development and/or progression of ADPKD.