Abstract: SA-PO323

Melatonin Ameliorates Intrarenal Renin-Angiotensin System in a 5/6 Nephrectomy Rat Model

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 308 CKD: Mechanisms of Tubulointerstitial Fibrosis

Authors

  • Ishigaki, Sayaka, Hamamatsu University School of Medicine , Hamamatsu, Japan
  • Ohashi, Naro, Hamamatsu University School of Medicine , Hamamatsu, Japan
  • Matsuyama, Takashi, Hamamatsu University School of Medicine , Hamamatsu, Japan
  • Isobe, Shinsuke, Hamamatsu University School of Medicine , Hamamatsu, Japan
  • Tsuji, Naoko, Hamamatsu University School of Medicine , Hamamatsu, Japan
  • Fujikura, Tomoyuki, Hamamatsu University School of Medicine , Hamamatsu, Japan
  • Tsuji, Takayuki, Hamamatsu University School of Medicine , Hamamatsu, Japan
  • Kato, Akihiko, Hamamatsu University School of Medicine , Hamamatsu, Japan
  • Yasuda, Hideo, Hamamatsu University School of Medicine , Hamamatsu, Japan
Background

Activation of the intrarenal renin-angiotensin system (RAS) plays a critical role in the pathophysiology of chronic kidney disease (CKD) and hypertension. Reactive oxygen species (ROS) are important components of intrarenal RAS activation and there has been great interest in developing strategies that target the ROS-RAS axis in the treatment of CKD. 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 RAS (angiotensinogen, angiotensin II type 1 receptors, and angiotensin II), 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 and type I collagen) in the remnant kidneys. Treatment with melatonin significantly reversed intrarenal RAS and ROS activation (angiotensin II positive area (%); Nx: 5.54 ± 0.44 vs. Nx+MEL: 2.99 ± 0.33, p<0.01 and superoxide dismutase (U/g tissue); Nx: 27.4 ± 3.0 vs. Nx+MEL: 42.4 ± 3.2, p=0.011), decreased blood pressure (systolic blood pressure (mmHg); Nx: 203.5±8.7 vs. Nx+MEL: 173.0 ± 8.7, p=0.049), and ameliorated interstitial fibrosis (α-smooth muscle actin (%); Nx: 2.76 ± 0.37 vs. Nx+MEL: 1.51 ± 0.21, p=0.033).

Conclusion

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