AI Article Synopsis
- The study investigates how corticosteroids, specifically aldosterone (ALDO) and corticosterone (CORT), regulate sodium reabsorption through the epithelial sodium channel (ENaC) in specialized kidney cells (mCCD).
- A total of nine genes were found to be affected by ALDO, while CORT had an effect only when 11βHSD2, an enzyme that normally protects against its activity, was inhibited, revealing a complex regulatory mechanism.
- The researchers used advanced techniques, such as RNA sequencing and a novel reporter mouse model, to confirm the physiological relevance of their findings and validate three new genes that respond to ALDO in the context of ENaC activity.
Article Abstract
Key Points: We report the transcriptomes associated with acute corticosteroid regulation of ENaC activity in polarized mCCD collecting duct cells. Nine genes were regulated by aldosterone (ALDO), 0 with corticosterone alone, and 151 with corticosterone when 11βHSD2 activity was inhibited. We validated three novel ALDO-induced genes, , , and , in primary cells isolated from a novel principal cell reporter mouse.
Background: Corticosteroids regulate distal nephron and collecting duct (CD) Na reabsorption, contributing to fluid-volume and blood pressure homeostasis. The transcriptional landscape underpinning the acute stimulation of the epithelial sodium channel (ENaC) by physiological concentrations of corticosteroids remains unclear.
Methods: Transcriptomic profiles underlying corticosteroid-stimulated ENaC activity in polarized mCCD cells were generated by coupling electrophysiological measurements of amiloride-sensitive currents with RNAseq. Generation of a principal cell-specific reporter mouse line, -Aqp2Cre, enabled isolation of primary CD principal cells by FACS, and ENaC activity was measured in cultured primary cells after acute application of corticosteroids. Expression of target genes was assessed by qRT-PCR in cultured cells or freshly isolated cells after the acute elevation of steroid hormones in -Aqp2Cre mice.
Results: Physiological relevance of the mCCD model was confirmed with aldosterone (ALDO)-specific stimulation of SGK1 and ENaC activity. Corticosterone (CORT) only modulated these responses at supraphysiological concentrations or when 11βHSD2 was inhibited. When 11βHSD2 protection was intact, CORT caused no significant change in transcripts. We identified a small number of ALDO-induced transcripts associated with stimulated ENaC activity in mCCD cells and a much larger number with CORT in the absence of 11βHSD2 activity. Principal cells isolated from -Aqp2Cre mice were validated and assessment of identified ALDO-induced genes revealed that , , , , and are acutely upregulated by corticosteroids both and .
Conclusions: This study reports the transcriptome of mCCD cells and identifies a small number of ALDO-induced genes associated with acute stimulation of ENaC, including three previously undescribed genes.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10103384 | PMC |
| http://dx.doi.org/10.34067/KID.0003582022 | DOI Listing |
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