Potential role of renal mineralocorticoid receptor increasing the blood pressure sensitivity in female mice exposed to early life stress (ELS)
Authors: Murphy Margaret O , Cohn Dianne , Loria Analia S 
Published: November 2023

Epidemiological studies have shown that exposure to ELS increases the number of risk factors to develop cardiovascular and metabolic disease later in life. Previously, we have shown that C57BL/6 mice exposed to maternal separation (MatSep), a model of ELS, display exaggerated diet‐induced obesity. However, only female MatSep mice show increased visceral fat and glucose intolerance compared to male MatSep mice. In addition, we have reported increased local glucocorticoid regeneration in liver and adipose tissue as a potential mechanism of ELS‐induced obesity. The aim of this study was to investigate the impact of MatSep in combination with a high fat diet (HFD) on blood pressure and renal gene expression of the glucocorticoid receptor (GR), mineralocorticoid receptor (MR) and 11 β‐hydroxysteroid dehydrogenase types 1 and 2. MatSep was performed in C57BL/6 mice pups by daily separation from the dam during the first two weeks of life. Non‐disturbed litters were used as controls. Upon weaning, mice were fed a HFD (60% kcal from fat) for 16 weeks. Female mice were implanted with radiotelemetry at week 14 (DSI, n=4–5). Whole kidney tissue from female mice was collected and snap frozen for gene expression determination using RT‐PCR (n=6–8). Mean arterial pressure (24hr average) was elevated in female MatSep mice compared to control (133.1±0.1 vs. 122.8±0.7 mmHg, p<0.05). Pulse pressure was increased in MatSep mice as well (35.1±0.1 vs. 31.4±0.4 mmHg, p<0.05). No differences were observed in HR (622.2±21.6 vs. 638.1±28.5 bpm, p<0.05); however, spontaneous baroreflex sensitivity was reduced in female mice exposed to MatSep (1.67±0.18 vs. 2.52±0.24 msec/mmHg, p<0.05). Renal expression levels of 11βHSD1 were similar in female MatSep and control mice fed a HFD. Yet, 11βHSD2 mRNA expression was attenuated in female MatSep mice compared to control mice (0.6±0.1 vs. 1.0±0.1 fold, p<0.05). GR expression was similar between groups but MR expression was reduced in MatSep mice vs. control (0.5±0.1 vs. 1.0±0.1 fold, respectively, p<0.05). Additional experiments revealed that MatSep had no effect on renal 11βHSD1 or 11βHSD2 mRNA expression in male mice. Furthermore, no differences in gene expression were observed between MatSep and control groups when the mice were fed a low fat diet. Interestingly, estrogen receptor β (ERβ) mRNA expression in the kidney was significantly upregulated in obese female MatSep mice (3.8±0.3 vs. 1.1±0.2 fold, respectively, p<0.05), with no differences in ERα expression. Since the analysis of the 11βHSD2 promoter revealed 4 estrogen response elements ~50,000 bp near to its start point, further investigation in the control of this enzyme by estradiol will be conducted. Taken together, these data suggest that in response to a second hit such as HFD, MatSep may induce MR overstimulation leading to increases in blood pressure sensitivity in female mice.Support or Funding InformationNIH R00 HL111354; COBRE P20 GM103527‐06