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Knockout of the Circadian Clock Protein PER1 (Period1) Exacerbates Hypertension and Increases Kidney Injury in Dahl Salt-Sensitive Rats.


ABSTRACT:

Background

Circadian rhythms play an essential role in physiological function. The molecular clock that underlies circadian physiological function consists of a core group of transcription factors, including the protein PER1 (Period1). Studies in mice show that PER1 plays a role in the regulation of blood pressure and renal sodium handling; however, the results are dependent on the strain being studied. Using male Dahl salt-sensitive (SS) rats with global knockout of PER1 (SSPer1-/-), we aim to test the hypothesis that PER1 plays a key role in the regulation of salt-sensitive blood pressure.

Methods

The model was generated using CRISPR/Cas9 and was characterized using radiotelemetry and measures of renal function and circadian rhythm.

Results

SSPer1-/- rats had similar mean arterial pressure when fed a normal 0.4% NaCl diet but developed augmented hypertension after three weeks on a high-salt (4% NaCl) diet. Despite being maintained on a normal 12:12 light:dark cycle, SSPer1-/- rats exhibited desynchrony mean arterial pressure rhythms on a high-salt diet, as evidenced by increased variability in the time of peak mean arterial pressure. SSPer1-/- rats excrete less sodium after three weeks on the high-salt diet. Furthermore, SSPer1-/- rats exhibited decreased creatinine clearance, a measurement of renal function, as well as increased signs of kidney tissue damage. SSPer1-/- rats also exhibited higher plasma aldosterone levels.

Conclusions

Altogether, our findings demonstrate that loss of PER1 in Dahl SS rats causes an array of deleterious effects, including exacerbation of the development of salt-sensitive hypertension and renal damage.

SUBMITTER: Zietara A 

PROVIDER: S-EPMC9669134 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Knockout of the Circadian Clock Protein PER1 (Period1) Exacerbates Hypertension and Increases Kidney Injury in Dahl Salt-Sensitive Rats.

Zietara Adrian A   Spires Denisha R DR   Juffre Alexandria A   Costello Hannah M HM   Crislip G Ryan GR   Douma Lauren G LG   Levchenko Vladislav V   Dissanayake Lashodya V LV   Klemens Christine A CA   Nikolaienko Oksana O   Geurts Aron M AM   Gumz Michelle L ML   Staruschenko Alexander A  

Hypertension (Dallas, Tex. : 1979) 20220912 11


<h4>Background</h4>Circadian rhythms play an essential role in physiological function. The molecular clock that underlies circadian physiological function consists of a core group of transcription factors, including the protein PER1 (Period1). Studies in mice show that PER1 plays a role in the regulation of blood pressure and renal sodium handling; however, the results are dependent on the strain being studied. Using male Dahl salt-sensitive (SS) rats with global knockout of PER1 (SS<sup>Per1-/-  ...[more]

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