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Abstract: FR-PO503

Mechanisms of Renal Potassium Handling Sexual Dimorphism Resolved at Single-Cell Level

Session Information

Category: Fluid, Electrolytes, and Acid-Base Disorders

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

Authors

  • Jung, Hyun Jun, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Grimm, Rick, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Welling, Paul A., The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Al-Qusairi, Lama, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
Background

A recent study revealed a rising trend of hypokalemia in the US general population, with women being more prone to hypokalemia. Our previous study revealed that the response to potassium (K+) deficiency in mice phenocopies the human condition, with females being more susceptible to hypokalemia than males upon dietary K+ deprivation.

Methods

C57BL6J wild-type male and female mice were randomized to a control or K+-free diet for 8 days. K+ balance and key transporters involved in renal K+ secretion were analyzed. The sexual dimorphic transcriptional responses to K+ deprivation were assessed using single nucleus RNA-Seq (snRNA-Seq) in whole kidneys.

Results

Males exhibited a more robust reduction in renal K+ excretion in response to K+ deprivation compared with females. The apical localization of K+-secretory ROMK channel in the early distal nephron was less abundant in males under basal conditions and decreased to a greater extent than in females in response to K+ deprivation. snRNA-Seq of whole kidneys from both sexes defined 45 cell-type clusters. Given the key role of the distal nephron in K+ regulation, we initially analyzed distal tubular cells. Cell type-dependent transcriptome profiling revealed that connecting tubule (CNT) cells exhibited striking sex-dependent changes in response to K+ deprivation. Pathway enrichment analysis of the CNT differentially expressed genes (DEGs) between control and K+-deprived animals revealed that cellular processes associated with the cytoskeleton and actin organization were mostly reprogrammed in females, while ion channel regulating pathways exhibited more active reprogramming in males. Among the DEGs, transcript abundance of the Kl gene encoding for Klotho protein, a positive regulator of ROMK, was significantly decreased in K+-deprived males only. Similar to the transcript levels, Klotho protein was significantly decreased in response to K+ deprivation only in males, consistent with more robust reduction in ROMK, leading to more efficient K+ conservation in males.

Conclusion

Females are more susceptible to hypokalemia due to urinary K+ loss. This sexual dimorphism is mediated by sex-dependent gene reprogramming of the CNT. Specifically, ROMK and its regulatory network, including Klotho, are involved in shaping the sexual dimorphism of K+ regulation.

Funding

  • Other NIH Support