Clinical and Experimental Nephrology

, Volume 22, Issue 3, pp 539–549 | Cite as

Melatonin ameliorates intrarenal renin–angiotensin system in a 5/6 nephrectomy rat model

  • Sayaka Ishigaki
  • Naro Ohashi
  • Takashi Matsuyama
  • Shinsuke Isobe
  • Naoko Tsuji
  • Takamasa Iwakura
  • Tomoyuki Fujikura
  • Takayuki Tsuji
  • Akihiko Kato
  • Hiroaki Miyajima
  • Hideo Yasuda
Original article



Activation of the intrarenal renin–angiotensin system (RAS) plays a critical role in the pathophysiology of chronic kidney disease (CKD) and hypertension. It has been reported that reactive oxygen species (ROS) are important components of intrarenal RAS activation. Melatonin is recognized as a powerful antioxidant, and we recently reported that impaired nighttime melatonin secretion correlates negatively with urinary angiotensinogen excretion, the surrogate marker of intrarenal RAS activity in patients with CKD. However, whether melatonin supplementation ameliorates the augmentation of intrarenal RAS in CKD has remained unknown. We aimed to clarify whether exogenous melatonin ameliorates intrarenal RAS activation via the reduction of ROS production.


5/6 Nephrectomized (Nx) rats were used as a chronic progressive CKD model and compared with sham-operated control rats. The Nx rats were divided into untreated Nx rats and melatonin-treated Nx rats. The levels of intrarenal RAS, ROS components, and renal injury were evaluated after 4 weeks of treatment.


Compared with the control rats, the untreated Nx rats exhibited significant increases in intrarenal angiotensinogen, angiotensin II (AngII) type 1 receptors, and AngII, accompanied by elevated blood pressure, higher oxidative stress (8-hydroxy-2′-deoxyguanosine), lower antioxidant (superoxide dismutase) activity, and increased markers of interstitial fibrosis (α-smooth muscle actin, Snail, and type I collagen) in the remnant kidneys. Treatment with melatonin significantly reversed these abnormalities.


Antioxidant treatment with melatonin was shown to ameliorate intrarenal RAS activation and renal injury in a 5/6 Nx rat model.


Melatonin Intrarenal renin–angiotensin system Oxidative stress 5/6 Nephrectomy Blood pressure Chronic kidney disease 



This study was supported by grants from Young Investigator Research Projects of Hamamatsu University School of Medicine in 2015 (Awarded to Sayaka Ishigaki).

Compliance with ethical standards

Conflict of interest

The authors have no conflicts of interest to declare.

Ethical approval

All procedures performed in studies involving animals were in accordance with the ethical standards of the Animal Committee of the Hamamatsu University School of Medicine (No. 2015088).

Supplementary material

10157_2017_1505_MOESM1_ESM.pdf (156 kb)
Supplementary material 1 (PDF 155 kb)


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Copyright information

© Japanese Society of Nephrology 2017

Authors and Affiliations

  • Sayaka Ishigaki
    • 1
  • Naro Ohashi
    • 1
  • Takashi Matsuyama
    • 1
  • Shinsuke Isobe
    • 1
  • Naoko Tsuji
    • 2
  • Takamasa Iwakura
    • 1
  • Tomoyuki Fujikura
    • 1
  • Takayuki Tsuji
    • 1
  • Akihiko Kato
    • 2
  • Hiroaki Miyajima
    • 1
  • Hideo Yasuda
    • 1
  1. 1.Internal Medicine 1Hamamatsu University School of MedicineHamamatsuJapan
  2. 2.Blood Purification UnitHamamatsu University School of MedicineHamamatsuJapan

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