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Nobiletin resolves left ventricular and renal changes in 2K-1C hypertensive rats

Metee Iampanichakul1, Anuson Poasakate1, Prapassorn Potue1

  • 1Department of Physiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand.

Scientific Reports
|June 6, 2022
PubMed

Insights

Nobiletin effectively lowers blood pressure and improves heart and kidney function in hypertensive rats by inhibiting the renin-angiotensin system and reducing oxidative stress. It also mitigates cardiac and renal damage through specific molecular pathways.

Area of Science:

  • Cardiovascular Research
  • Nephrology
  • Pharmacology

Background:

  • Two-kidney, one-clip (2K-1C) hypertension is a model of renovascular hypertension characterized by elevated blood pressure and cardiorenal complications.
  • The renin-angiotensin system (RAS) plays a critical role in the pathogenesis of 2K-1C hypertension.
  • Nobiletin, a citrus flavonoid, has demonstrated potential therapeutic properties, but its effects on cardiorenal changes in hypertension require further investigation.

Purpose of the Study:

  • To investigate the therapeutic effects of nobiletin on cardiorenal alterations in a 2K-1C rat model of hypertension.
  • To elucidate the underlying molecular mechanisms, including RAS modulation, oxidative stress, and specific signaling pathways, involved in nobiletin's actions.

Main Methods:

  • 2K-1C hypertensive rats were treated with nobiletin (15 or 30 mg/kg/day) or losartan for four weeks.
  • Hemodynamic parameters, including blood pressure, were monitored.
  • Cardiac and renal tissues were analyzed for molecular changes, including protein expression of Angiotensin II type 1 receptor (AT1R), Janus kinase (JAK), signal transducer and activator of transcription (STAT), and NADPH oxidase 4 (Nox4).
  • Oxidative stress markers and antioxidant enzyme activity were assessed.

Main Results:

  • Nobiletin treatment significantly reduced blood pressure, circulating angiotensin II, and angiotensin-converting enzyme activity in 2K-1C rats.
  • Nobiletin alleviated left ventricular dysfunction and cardiac remodeling by restoring the AT1R/JAK/STAT pathway.
  • Renal function was improved, and renal fibrosis was reduced by nobiletin, associated with the suppression of AT1R and Nox4 in kidney tissue.
  • Nobiletin attenuated oxidative stress and enhanced antioxidant capacity in hypertensive rats.

Conclusions:

  • Nobiletin exhibits significant antihypertensive effects in the 2K-1C rat model.
  • Nobiletin exerts cardiorenal protective effects through inhibition of the renin-angiotensin system and reduction of oxidative stress.
  • The therapeutic actions of nobiletin involve the modulation of the AT1R/JAK/STAT and AT1R/Nox4 signaling pathways, highlighting its potential as a novel therapeutic agent for hypertension-related cardiorenal complications.

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