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Zietara, Adrian; Spires, Denisha R.; Juffre, Alexandria; Costello, Hannah M.; Crislip, G. Ryan; Douma, Lauren G.; Levchenko, Vladislav; Dissanayake, Lashodya V.; Klemens, Christine A.; Nikolaienko, Oksana; Geurts, Aron M.; Gumz, Michelle L.; Staruschenko, Alexander

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

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  • Media type: E-Article
  • Title: Knockout of the Circadian Clock Protein PER1 (Period1) Exacerbates Hypertension and Increases Kidney Injury in Dahl Salt-Sensitive Rats
  • Contributor: Zietara, Adrian; Spires, Denisha R.; Juffre, Alexandria; Costello, Hannah M.; Crislip, G. Ryan; Douma, Lauren G.; Levchenko, Vladislav; Dissanayake, Lashodya V.; Klemens, Christine A.; Nikolaienko, Oksana; Geurts, Aron M.; Gumz, Michelle L.; Staruschenko, Alexander
  • imprint: Ovid Technologies (Wolters Kluwer Health), 2022
  • Published in: Hypertension
  • Language: English
  • DOI: 10.1161/hypertensionaha.122.19316
  • ISSN: 0194-911X; 1524-4563
  • Keywords: Internal Medicine
  • Origination:
  • Footnote:
  • Description: <jats:sec> <jats:title>Background:</jats:title> <jats:p> 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 <jats:sup>Per1−/−</jats:sup> ), we aim to test the hypothesis that PER1 plays a key role in the regulation of salt-sensitive blood pressure. </jats:p> </jats:sec> <jats:sec> <jats:title>Methods:</jats:title> <jats:p>The model was generated using CRISPR/Cas9 and was characterized using radiotelemetry and measures of renal function and circadian rhythm.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p> SS <jats:sup>Per1−/−</jats:sup> 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, SS <jats:sup>Per1−/−</jats:sup> 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. SS <jats:sup>Per1−/−</jats:sup> rats excrete less sodium after three weeks on the high-salt diet. Furthermore, SS <jats:sup>Per1−/−</jats:sup> rats exhibited decreased creatinine clearance, a measurement of renal function, as well as increased signs of kidney tissue damage. SS <jats:sup>Per1−/−</jats:sup> rats also exhibited higher plasma aldosterone levels. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>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.</jats:p> </jats:sec>
  • Access State: Open Access