Sex‐specific Impairment of Diurnal Renal Na+ Excretion in Obese Sprague‐Dawley Rats

Abstract

The role of the renal endothelin system in obesity is poorly understood despite playing a key role in excreting a high salt diet. Sodium excretion follows a diurnal rhythm that is controlled by central and peripheral clock genes. The aim of this study was to determine whether the renal endothelin system is disrupted in obesity and interferes with the diurnal rhythm of Na+ excretion. Our overarching hypothesis is that diet‐induced obesity impairs salt handling in a time of day‐dependent manner through renal endothelin dysfunction. Male and female Sprague‐Dawley rats were put on either 45 Kcal% fat (high fat, HF) or control 10 Kcal% fat (normal fat, NF) diet starting at 6 weeks of age. After 8 weeks, rats were put in metabolic cages for 2 days of acclimation, followed by 12‐hour collections of baseline urine output, food and water intake for an additional 2 days. On day 5, rats were given an acute salt load of (900 mEq NaCl in 1ml H2O, i.p.) either at the beginning of their inactive period (Zeitgeber time 0, ZT0) or active period (Zeitgeber time 12, ZT12). Urine was collected over the following 24 hours in 12‐hour intervals. Both male and female rats on HF diet showed significantly greater body weights (414 ± 6 vs 386 ± 6 gm in males, n= 12 and 303 ± 9 vs 266 ± 7 gm in females, n= 8) and total body fat measured by QMR (10.8 ± 0.5 vs 6.7 ± 0.4% in males, n= 12 and 15.3 ± 0.9 vs 9.8 ± 0.5% in females, n= 8) compared to NF controls. Male rats on HF given salt load at ZT0 showed similar urine and Na+ excretion (UNaV) rates compared to lean controls (DUNaV was 395 ± 46 vs 496 ± 71 μEq/12 hrs in the first 12 hours post‐load, n= 12). However, HF rats showed significantly delayed natriuresis in response to ZT12 salt load (DUNaV was 605 ± 98 vs 960 ± 59 μEq/12 hrs in the first 12 hours post‐load, n= 8). On the other hand, obese female rats showed an intact natriuretic response at both ZT0 (772 ± 32 vs 673 ± 84 μEq/12 hrs in the first 12 hours post‐load, n= 8) and ZT12 (671 ± 153 vs 801. ± 106 μEq/12 hrs in the first 12 hours post‐load, n=8) compared to NF. Assessment of urinary endothelin‐1 (ET1) showed significantly decreased active period ET1 excretion rates in obese males (0.3 ± 0.04 vs 0.3 ± 0.04 pg/12 hrs inactive and 0.8 ± 0.1 vs 1.5 ± 0.1 pg/12 hrs active period, n=11) and following salt challenge (0.9 ± 0.1 vs 1.7 ± 0.2 pg/12 hrs in the second 12 hrs of ZT0 salt load and 1.5 ± 0.1 vs 2.7 ± 0.1 pg/12 hrs in the first 12 hrs of ZT12 salt load, n=11). The reduced ET1 in the HF group was evident during their active period, while inactive period ET1 was similar among groups. Obese female rats, on the other hand, showed comparable urine ET1 values to their lean control, at both baseline (0.5 ± 0.2 vs 0.3 ± 0.1 pg/12 hrs at inactive and 1.1 ± 0.2 vs 1.4 ± 0.2 pg/12 hrs at active period, n=5) and following the acute salt load regardless of time of day (0.8 ± 0.1 vs 0.7 ± 0.1 pg/12 hrs at ZT0 and 1.3 ± 0.3 vs 1.6 ± 0.1 pg/12 hrs at ZT12). In conclusion, our study shows that impairment of sodium excretion in obesity is time‐of‐day and sex‐dependent. It also shows a strong correlation between renal endothelin‐1 dysfunction and impaired Na+ excretion in obese male Sprague‐Dawley ratsSupport or Funding InformationP01 HL136267 to DMPThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.