Sex‐Differences in Renal Na+ Regulatory Mechanisms During Acclimation to a High Salt Diet

Abstract

Hypertension is more prevalent in men compared to premenopausal women. Maintenance of Na+ homeostasis is an essential component of blood pressure regulation, and defects in the renal capacity to appropriately excrete Na+ are fundamental mechanisms involved in the initiation of salt‐sensitive hypertension. We recently reported that female rats elicit a more rapid natriuretic response to a high salt (HS) diet compared to males. The overall goal of the current study was to determine the natriuretic signaling pathway(s) involved in the enhanced ability of females to handle HS challenges. Male and female Sprague Dawley rats (16–18 weeks old) were placed into metabolic cages on normal salt (NS, 0.49% NaCl) followed by HS (4% NaCl) diet for 5 days. 24‐hour urine samples were assessed for endothelin‐1 (ET‐1), aldosterone (ALD) and norepinephrine (NE). On NS, urinary ET‐1 was significantly higher in females, compared to males; no sex‐differences were detected in urinary ALD or NE. In males, urinary ET‐1 was increased (10.2±0.8 vs. 5.6±1.0 pg/kg/day, n=8 each, p=0.002) and urinary ALD was decreased on day 1 HS relative to NS (6.1±0.7 vs. 15.2±2.6 μg/kg/day, n=5 each, p=0.02); no significant changes were observed in ET‐1 or ALD in females on day 1 HS. Urinary NE remained unchanged during the HS challenge in both sexes. Ingenuity Pathway Analysis (IPA) of RNA sequencing data from inner medullae from males and females on NS identified an enrichment (p=3.11E‐04) of transcripts in the ET‐1 signaling pathway in females, with the abundance of 35/190 (18.4%) of pathway transcripts being at least 1.5‐fold different in abundance between sexes. Further, IPA predicted that ET‐1 signaling is activated in female inner medulla, relative to males. Previous studies showed that interleukin‐1β (IL‐1β) stimulates renal ET‐1 production. Thus we tested whether renal IL‐1β is upregulated in response to HS in a sex‐dependent manner. Renal IL‐1β was assessed by ELISA and IHC. Renal cortical IL‐1β was significantly increased on day 1 HS, relative to NS, only in males (8.1±0.3 vs. 6.4±0.3 pg/mg protein, n=9 each, p=0.03). Our data suggest that activation of IL‐1β/ET‐1 and inhibition of ALD signaling pathways contribute to acclimation to HS challenges in males. We further suggest that the already activated renal ET‐1 signaling in females under NS may contribute to the enhanced ability to acclimate to HS challenges observed in females.Support or Funding InformationFunded by AHA 18CDA34110010 and 15POST25090329 to EYG, and P01 HL136267 to JSP and DMP. We appreciate Drs. Celso and Elise Gomez‐Sanchez's help with ALD assay.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.