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Circadian rhythm of the intrarenal renin–angiotensin system is caused by glomerular filtration of liver-derived angiotensinogen depending on glomerular capillary pressure in adriamycin nephropathy rats

Hypertension Research volume 44, pages 618–627 (2021)Cite this article

Abstract

Circadian fluctuation disorder of the intrarenal renin–angiotensin system (RAS) causes that of blood pressure (BP) and renal damage. In renal damage with an impaired glomerular filtration barrier, liver-derived angiotensinogen (AGT) filtered through damaged glomeruli regulates intrarenal RAS activity. Furthermore, glomerular permeability is more strongly affected by glomerular hypertension than by systemic hypertension. Thus, we aimed to clarify whether the circadian rhythm of intrarenal RAS activity is influenced by AGT filtered through damaged glomeruli due to glomerular capillary pressure. Rats with adriamycin nephropathy and an impaired glomerular filtration barrier were compared with control rats. In adriamycin nephropathy rats, olmesartan medoxomil (an angiotensin II type 1 receptor blocker) or hydralazine (a vasodilator) was administered, and the levels of intrarenal RAS components in the active and rest phases were evaluated. Moreover, the diameter ratio of afferent to efferent arterioles (A/E ratio), an indicator of glomerular capillary pressure, and the glomerular sieving coefficient (GSC) based on multiphoton microscopy in vivo imaging, which reflects glomerular permeability, were determined. Mild renal dysfunction was induced, and the systemic BP increased, resulting in increased A/E ratios in the adriamycin nephropathy rats compared with the control rats. Fluctuations in intrarenal RAS activity occurred in parallel with circadian fluctuations in glomerular capillary pressure, which disappeared with olmesartan treatment and were maintained with hydralazine treatment. Furthermore, the GSCs for AGT also showed similar changes. In conclusion, intrarenal RAS activity is influenced by the filtration of liver-derived AGT from damaged glomeruli due to circadian fluctuation disorder of the glomerular capillary pressure.

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Acknowledgements

We acknowledge Dr Kengo Kidokoro (Kawasaki Medical School), Dr Daisuke Nakano (Kagawa University), Dr Chiharu Uchida (Hamamatsu University School of Medicine), and Dr Toshiyuki Ojima (Hamamatsu University School of Medicine) for critical technical support and important advice. We also acknowledge Daiichi Sankyo Co. (Tokyo, Japan) for providing olmesartan medoxomil (CS-866). This study was supported by a Grant-in-Aid for Scientific Research (17K09693 to NO) from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and by grants from the Young Investigator Research Projects of Hamamatsu University School of Medicine in 2018 (awarded to TM).

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

    Takashi Matsuyama, Naro Ohashi, Taro Aoki, Shinsuke Isobe, Taichi Sato, Tomoyuki Fujikura, Hiroaki Miyajima & Hideo Yasuda

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

    Sayaka Ishigaki & Akihiko Kato

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  1. Takashi Matsuyama
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Matsuyama, T., Ohashi, N., Aoki, T. et al. Circadian rhythm of the intrarenal renin–angiotensin system is caused by glomerular filtration of liver-derived angiotensinogen depending on glomerular capillary pressure in adriamycin nephropathy rats. Hypertens Res 44, 618–627 (2021). https://doi.org/10.1038/s41440-021-00620-6

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