Abstract: SA-PO1106

Reciprocal Regulation between the Renal Endothelin and Circadian Rhythm Systems

Session Information

  • Salt and Hypertension
    November 04, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Hypertension

  • 1104 Hypertension: Clinical and Translational - Salt and Hypertension

Authors

  • Gumz, Michelle L., University of Florida, Gainesville, Florida, United States
  • Douma, Lauren G, University of Florida, Gainesville, Florida, United States
  • Lynch, I. Jeanette, University of Florida, Gainesville, Florida, United States
  • Solocinski, Kristen, University of Florida, Gainesville, Florida, United States
  • Cheng, Kit-yan, University of Florida, Gainesville, Florida, United States
  • Cain, Brian D., University of Florida, Gainesville, Florida, United States
  • Wingo, Charles S., University of Florida, Gainesville, Florida, United States
Background

Mice lacking the circadian rhythm gene Per1 exhibit non-dipping hypertension in response to a high salt diet plus mineralocorticoid treatment (HS/DOCP). We hypothesized that Per1 knockout (KO) mice have a renal Na handling defect involving ET-1 that contributes to non-dipping hypertension. ET-1 can mediate renal injury in salt-sensitive hypertension.

Methods

Twelve hour urine collections were made in metabolic cages to determine the night:day ratio of urine Na excretion in WT vs. Per1 KO mice in response to HS/DOCP. We assessed Per1 transcriptional activity using quantitative real time RT-PCR. Kidney cortex RNA was collected from WT and Per1 KO mice on control or HS/DOCP treatment at noon, the time when BP dips in WT mice but remains high in Per1 KO mice.

Results

WT mice exhibited a high night:day ratio of Na excretion but, Per1 KO had a significant reduction in the night:day Na excretion ratio (WT:6, KO:2, P<0.05). To explore the molecular mechanisms underlying this phenotype, we examined expression of Edn1 which encodes the peptide hormone endothelin-1 (ET-1). ET-1 mRNA levels did not change in WT in response to HS/DOCP. In contrast, Per1 KO mice exhibited increased expression of ET-1 mRNA in the renal cortex (40% increase, p<0.01). To test the hypothesis that there is reciprocal regulation between ET-1 and the molecular clock, we measured Per1 mRNA expression in the kidneys of collecting duct-specific ET-1 KO mice compared to WT controls after HS/DOCP treatment. Per1 expression was reduced by 50% in the renal medulla of CD ET-1 KO mice relative to WT mice (p<0.01).

Conclusion

The reduced night:day ratio in urine Na excretion suggest that a renal Na handling defect may contribute to non-dipping hypertension in Per1 KO mice. Per1 appears to be a negative regulator of ET-1 expression during HS/DOCP, whereas ET-1 may play a role in the positive regulation of Per1 expression. These data indicate that reciprocal regulation between renal ET-1 and the molecular clock, specifically Per1, occurs and may constitute a new feedback loop in mineralocorticoid-sensitive renal Na handling.

Funding

  • NIDDK Support