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

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Abstract

Background

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.

Methods

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.

Results

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.

Conclusion

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

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Acknowledgements

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

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Authors and Affiliations

  1. Internal Medicine 1, Hamamatsu University School of Medicine, 1-20-1 Handayama Higashi-ku, Hamamatsu, 431-3192, Japan

    Sayaka Ishigaki, Naro Ohashi, Takashi Matsuyama, Shinsuke Isobe, Takamasa Iwakura, Tomoyuki Fujikura, Takayuki Tsuji, Hiroaki Miyajima & Hideo Yasuda

  2. Blood Purification Unit, Hamamatsu University School of Medicine, 1-20-1 Handayama Higashi-ku, Hamamatsu, 431-3192, Japan

    Naoko Tsuji & Akihiko Kato

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  1. Sayaka Ishigaki
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Correspondence to Naro Ohashi.

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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).

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Ishigaki, S., Ohashi, N., Matsuyama, T. et al. Melatonin ameliorates intrarenal renin–angiotensin system in a 5/6 nephrectomy rat model. Clin Exp Nephrol 22, 539–549 (2018). https://doi.org/10.1007/s10157-017-1505-7

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