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American Heart Association

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Final ID: 39

Tryptophan contributes to the sex-dependent loss of diurnal sodium excretion in BMAL1 knockout rats.

Abstract Body: Kidney function is time-of-day-(TOD) dependent irrespective of light, sleep, activity, and meal timing. Recent discoveries reveal that diurnal (day/night) kidney function is maintained by an intrinsic molecular clock. We recently observed that loss of this transcriptional regulatory system impairs functional rhythms in electrolyte excretion in a novel rat model. When the core clock gene, brain and muscle ARNT-like protein 1 (BMAL1) is knocked out of Sprague-Dawley rats we now find that male, but not female, BMAL1 knockout (KO) rats no longer have diurnal changes in both glomerular filtration rate (GFR; Day:1.3±0.1 vs Night:1.2±0.1mL/min/100gBW;t-test p=0.919) along with sodium excretion (UNaV) (Day:819±58 vs Night:756±113 μmol/12h; t-test p=0.439) compared to littermate wildtype controls (CON; GFR Day:1.1±0.1 vs Night:1.6±0.1mL/min/100g; t-test p=0.044; UNaV Day: 849±138 vs Night:1423±102 μmol/12h; t-test p=0.003). LC/MS analysis of plasma from KO rats found that levels of tryptophan (trp) were significantly (2-way ANOVA pInteraction=0.847, pGenotype=0.041, pTimeofDay=0.952) lower in KO males during the day (KO:77±6, CON:99±7μM; Sidak post-hoc p=0.049) but not night (KO:78±5, CON:99±12μM; Sidak post-hoc p=0.084) with no differences in plasma trp seen in KO females (Day:110±26,107±14μM vs Night:96±8,96±12μM KO and CON respectively). Trp had recently been shown to both regulate and be regulated by the circadian clock as well as increase GFR similar to other aromatic amino acids. This led us to hypothesize that TOD trp availability may underlie the changes seen in both UNaV and GFR in male KO rats. Therefore, we gave a single dose of trp (100 mg/kg,PO) at either 7pm (lights off, ZT12) or 7am (lights on, ZT0). After a 1 wk washout period, rats were dosed again in a crossover design. Male KO rats receiving trp at ZT0 had no significant change from baseline in UNaV (818±58 vs 784±61 μmol/12h) over the following 12hrs; however, a significant increase in UNaV (756±114 vs 1152±146 μmol/12h) following ZT12 dosing was observed (2-Way ANOVA pInteraction=0.038, pTrpTime=0.087, pTimeofDay=0.210; Sidak Post-Hoc: baseline vs ZT12 trp p=0.003) with no significant change seen in female KO or either male or female CON rats. Taken together these results suggest that BMAL1 is necessary for maintaining kidney physiologic rhythms in sodium excretion potentially through changes in trp availability.
  • Latimer, Mary  ( UNIVERSITY OF ALABAMA BIRMINGHAM , Birmiham , Alabama , United States )
  • Pollock, David  ( University of Alabama at Birmingham , Birmingham , Alabama , United States )
  • Author Disclosures:
    Mary Latimer: DO NOT have relevant financial relationships | David Pollock: DO NOT have relevant financial relationships
Meeting Info:
Session Info:

15.A Renal hemodynamics, tubular transport, salt and renovascular hypertension

Saturday, 09/07/2024 , 10:30AM - 11:30AM

Oral Abstract Session

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