The renin-angiotensin system (RAS) is a major classic therapeutic target for cardiovascular diseases. In addition to the circulating RAS, local tissue RAS has been identified in various tissues and plays roles in tissue inflammation and tissue fibrosis. (Pro)renin receptor (PRR) was identified as a new member of RAS in 2002. Studies have demonstrated the effects of PRR and its soluble form in local tissue RAS. Moreover, as an important part of vacuolar H+-ATPase, it also contributes to normal lysosome function and cell survival. Evidently, PRR participates in the pathogenesis of cardiovascular diseases and may be a potential therapeutic target of cardiovascular diseases. This review focuses on the effects of PRR and its soluble form on the physiological state, hypertension, myocardial ischemia reperfusion injury, heart failure, metabolic cardiomyopathy, and atherosclerosis. We aimed to investigate the possibilities and challenges of PRR and its soluble form as a new therapeutic target in cardiovascular diseases.
Introduction
Obesity causes many life‐threatening diseases. It is important to develop effective approaches for obesity treatment. Oral supplementation with spermidine retards age‐related processes, but its influences on obesity and various metabolic tissues remain largely unknow. This study aims to investigate the effects of oral spermidine on brown adipose tissue (BAT) and skeletal muscle as well as its roles in counteracting obesity and metabolic disorders.
Methods and Results
Spermidine is orally administrated into high‐fat diet (HFD)‐fed mice. The weight gain, insulin resistance, and hepatic steatosis are attenuated by oral spermidine in HFD‐fed mice, accompanied by an alleviation of white adipose tissue inflammation. Oral spermidine promotes BAT activation and metabolic adaptation of skeletal muscle in HFD‐fed mice, evidenced by UCP‐1 induction and CREB activation in both tissues. Notably, oral spermidine upregulates tyrosine hydroxylase in hypothalamus of HFD‐fed mice; spermidine treatment increases tyrosine hydroxylase expression and norepinephrine production in neurocytes, which leads to CREB activation and UCP‐1 induction in brown adipocytes and myotubes. Spermidine also directly promotes UCP‐1 and PGC‐1α expression in brown adipocytes and myotubes.
Conclusion
Spermidine serves as an oral supplement to attenuate obesity and metabolic disorders through hypothalamus‐dependent or ‐independent BAT activation and skeletal muscle adaptation.
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