Matsuyama Takashi, Ohashi Naro, Aoki Taro, Ishigaki Sayaka, Isobe Shinsuke, Sato Taichi, Fujikura Tomoyuki, Kato Akihiko, Miyajima Hiroaki, Yasuda Hideo
Internal Medicine 1, Hamamatsu University School of Medicine, 1-20-1 Handayama Higashi-ku, Hamamatsu, 431-3192, Japan.
Blood Purification Unit, Hamamatsu University School of Medicine, 1-20-1 Handayama Higashi-ku, Hamamatsu, 431-3192, Japan.
Hypertens Res. 2021 Jun;44(6):618-627. doi: 10.1038/s41440-021-00620-6. Epub 2021 Feb 8.
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.
肾内肾素 - 血管紧张素系统（RAS）的昼夜节律紊乱会导致血压（BP）波动和肾损伤。在肾小球滤过屏障受损的肾损伤中，经受损肾小球滤过的肝脏源性血管紧张素原（AGT）调节肾内RAS活性。此外，肾小球通透性受肾小球高血压的影响比受全身性高血压的影响更强。因此，我们旨在阐明肾内RAS活性的昼夜节律是否受因肾小球毛细血管压力导致的经受损肾小球滤过的AGT的影响。将阿霉素肾病且肾小球滤过屏障受损的大鼠与对照大鼠进行比较。在阿霉素肾病大鼠中，给予奥美沙坦酯（一种血管紧张素II 1型受体阻滞剂）或肼屈嗪（一种血管扩张剂），并评估活动期和静息期肾内RAS成分的水平。此外，测定了肾小球毛细血管压力指标入球小动脉与出球小动脉直径比（A/E比），以及基于体内多光子显微镜成像反映肾小球通透性的肾小球筛滤系数（GSC）。诱导了轻度肾功能不全且全身血压升高，导致阿霉素肾病大鼠的A/E比相对于对照大鼠增加。肾内RAS活性的波动与肾小球毛细血管压力的昼夜波动平行发生，奥美沙坦治疗后这种波动消失，而肼屈嗪治疗后这种波动得以维持。此外，AGT的GSC也显示出类似变化。总之，由于肾小球毛细血管压力的昼夜节律紊乱，肾内RAS活性受来自受损肾小球的肝脏源性AGT滤过的影响。
