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5/6th Nephrectomy in Combination with High Salt Diet and Nitric Oxide Synthase Inhibition to Induce Chronic Kidney Disease in the Lewis Rat
Published on: July 3, 2013
Melatonin ameliorates intrarenal renin-angiotensin system in a 5/6 nephrectomy rat model
Sayaka Ishigaki1, Naro Ohashi2, Takashi Matsuyama1
1Internal Medicine 1, Hamamatsu University School of Medicine, 1-20-1 Handayama Higashi-ku, Hamamatsu, 431-3192, Japan.
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.
Insights
Melatonin supplementation reduced intrarenal renin-angiotensin system (RAS) activation and kidney injury in a chronic kidney disease (CKD) rat model. This antioxidant treatment improved blood pressure and reduced oxidative stress, offering potential therapeutic benefits for CKD patients.
Area of Science:
- Nephrology
- Endocrinology
- Oxidative Stress Research
Background:
- The intrarenal renin-angiotensin system (RAS) is crucial in chronic kidney disease (CKD) and hypertension.
- Reactive oxygen species (ROS) are key mediators of intrarenal RAS activation.
- Impaired melatonin secretion in CKD patients correlates with increased intrarenal RAS activity.
Purpose of the Study:
- To investigate if exogenous melatonin can mitigate intrarenal RAS activation in a CKD model.
- To determine if melatonin reduces ROS production, thereby ameliorating intrarenal RAS activation.
Main Methods:
- A 5/6 nephrectomized (Nx) rat model was used to simulate chronic progressive CKD.
- Nx rats were divided into untreated and melatonin-treated groups for 4 weeks.
- Intrarenal RAS components, ROS markers, and renal injury were assessed.
Main Results:
- Untreated Nx rats showed elevated intrarenal angiotensinogen, Angiotensin II type 1 receptors, AngII, blood pressure, and oxidative stress.
- Markers of interstitial fibrosis and reduced antioxidant activity (superoxide dismutase) were observed in untreated Nx rats.
- Melatonin treatment significantly reversed these adverse changes, including renal injury.
Conclusions:
- Melatonin, as an antioxidant, effectively ameliorates intrarenal RAS activation in a CKD rat model.
- The findings suggest melatonin's therapeutic potential for managing CKD and associated hypertension.
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