Kidney Week

Abstract: TH-PO0032

Potassium Deficiency Activates the GCN2-eIF2α Integrated Stress Response and Mediates AQP2 Loss in Collecting Ducts

Session Information

• Fluid, Electrolyte, and Acid-Base Disorders: Basic Research
  October 22, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Fluid, Electrolytes, and Acid-Base Disorders

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

Authors

• Sung, Chih-Chien, Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical University, Taipei, Taiwan

Chih-Chien Sung, MD, PhD

• Chen, Min-Hsiu, Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical University, Taipei, Taiwan

Min-Hsiu Chen, MS

• Hsu, Yu-Juei, Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical University, Taipei, Taiwan

Yu-Juei Hsu, MD, PhD

• Lin, Shih-Hua P., Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical University, Taipei, Taiwan

Shih-Hua P. Lin, MD

Background

Potassium (K⁺) deficiency can impair urinary concentration ability and lead to nephrogenic diabetes insipidus (NDI), but the underlying mechanism remains unclear. Recent transcriptomic and proteomic studies in acquired NDI rat models have suggested that inflammatory signaling is associated with AQP2 loss. We aim to investigate the early signaling induced by K⁺ deficiency in collecting ducts.

Methods

We performed RNA-Seq and LC-MS/MS on microdissected rat cortical collecting ducts (CCDs) to identify early signaling pathway after establishment of K⁺ deprivation mediating the loss of AQP2. The ideintifed signaling was further validated by the mpkCCD cells.

Results

RNA-Seq data of microdissected CCDs at 6 hours after K⁺ deprivation demonstrated significant downregulation of Aqp2, Aqp3, and Atp1a1. In contrast, chemokine transcripts (Ccl20 and Ccl28) were significantly upregulated. Gene Ontology Biological Process terms among statistically over-represented in the list of 88 “Increased Transcripts” are related to glutathione metabolic process, positive regulation of ERK1 and ERK2 cascade, cell chemotaxis, cellular response to lipopolysaccharide, consistent with an inflammatory response. LC-MS/MS analysis of microdissected CCDs at 12 hours after K⁺ deprivation identified upregulated EIF2S1, which was further confirmed by immunoblotting of rat kidney after K⁺ deprivation. In mpkCCD cells, Ccl20 and Cxcl16 significantly increased at 3 hours, whereas the Aqp2 markedly decreased at 18 hours after K⁺ deprivation compared with normal K⁺ medium (NK controls). Notably, p-GCN2 and p-eIF2α/eIF2α started to increase at 1 hour after K⁺ deprivation, supporting early activation of the GCN2–eIF2α integrated stress response pathway. To further confirm the role of GCN2 mediating K⁺ deprivation, GCN2 knockdown partially rescued AQP2 expression at 18 hours after K⁺ deprivation. In addition, N-acetylcysteine also partially restored AQP2 expression at 18 hours after K⁺ deprivation, indicating a potential role for reactive oxygen species related inflammation in mediating the loss of AQP2.

Conclusion

These findings identify activation of the GCN2–eIF2α integrated stress response as an early mechanism linking K⁺ deficiency to inflammatory signaling and AQP2 loss in collecting ducts.

Funding

• Government Support – Non-U.S.