Mild dehydration effects on the murine kidney single-nucleus transcriptome and chromatin accessibility

Area of Science:

• Renal physiology and molecular biology
• Genomics and epigenomics
• Sex-based differences in biological response

Background:

• Daily mild dehydration can increase plasma osmolality, triggering vasopressin release.
• While collecting duct principal cell responses to dehydration are known, broader kidney cell changes remain understudied.
• Investigating cell-specific transcriptomic and chromatin accessibility changes offers deeper insight into kidney adaptation.

Purpose of the Study:

• To investigate the effects of mild dehydration on kidney transcriptomes and chromatin accessibility across various cell types.
• To identify sex-specific molecular responses to dehydration in the kidney.
• To explore the relationship between gene expression and chromatin accessibility changes during dehydration.

Main Methods:

• Employed single-nucleus multiome sequencing (sn-multiome-seq) and bulk RNA sequencing on mouse kidneys.
• Compared kidneys from mildly water-deprived mice versus control mice (ad libitum water and food).
• Analyzed 19,837 nuclei across 33 annotated clusters, focusing on differentially expressed genes and chromatin accessibility.

Main Results:

• Mild dehydration significantly increased plasma osmolality and altered gene expression in kidney cells, including increased aquaporin 2 and 3 in collecting duct principal cells.
• Identified novel dehydration-responsive genes like gremlin 2 (Grem2) and increased accessibility of the CREM transcription factor binding motif.
• Revealed hundreds of sex- and dehydration-specific differentially expressed genes, with males showing enrichment in lipid metabolism and females in organic acid metabolism pathways.

Conclusions:

• Mild dehydration induces widespread, cell-specific transcriptomic and chromatin accessibility changes in the kidney.
• Significant sex-specific differences exist in kidney gene expression responses to dehydration, suggesting distinct regulatory mechanisms.
• These findings underscore the complexity of kidney fluid balance regulation and highlight the importance of considering sex in physiological studies.