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  • Canrenone Previous study demonstrated that Hcy elevated orga


    Previous study demonstrated that Hcy elevated organ culture-induced up-regulation of ETB receptor in VSMCs (Chen et al., 2016a; Chen et al., 2016b). Many signaling pathways were involved in Hcy-induced up-regulation of ETB receptor in VSMCs, such as ERK1/2/NF-κB signaling pathway, Sirt1/NF-κB signaling pathway. In present study, Hcy not only increased the levels of ETB receptor in SMA, but also inhibited organ culture-induced autophagy in SMA. The autophagy may be a novel pathway, which mediated Hcy-induced up-regulation of ETB receptor in VSMCs. The AMPK is a serine/threonine protein kinase. The heterotrimeric protein AMPK is formed by α, β, and γ subunits. Each of these three subunits has a specific role in both the stability and activity of AMPK (Stapleton et al., 1996). AMPK activation induces autophagy through several signaling pathways (Zhang et al., 2016; Shin et al., 2016; Pan et al., 2016). In present study, Hcy significantly decreased the levels of p-AMPK α in SMA. However, AICAR elevated Hcy-decreased the level of p-AMPK in SMA. Moreover, AICAR not only improve Hcy-impaired autophagy, but also down-regulated Hcy-increased levels of ETB receptor in SMA. This demonstrated that Hcy up-reguated ETB receptors by inhibiting autophagy in VSMCs via activation of AMPK. The mTOR is a regulator of inhibition of autophagy. mTOR is important downstream of AMPK, which is a negative regulator of mTOR signaling (Bolster et al., 2002). Rap, a well-known specific inhibitor of mTOR, which has been found to induce the autophagy process (Wullschleger et al., 2005). In present study, Hcy significantly increased the levels of p-mTOR in SMA. However, Rap inhibited Hcy-increased the level of p-mTOR in SMA. Furthermore, Rap not only improved Hcy-impaired autophagy, but also down-reguated Hcy-increased levels of ETB receptor in SMA. This demonstrated that Hcy up-reguated ETB receptors by inhibiting autophagy in VSMCs via inhibition of mTOR. In addition, recent study also found that MHY1485 significantly recovered AICAR-inhibited the levesl of ETB receptor protein Canrenone in Hcy group. This suggested that Hcy inhibited AMPK, and activated mTOR, followed by up-regulating ETB receptor.
    Conclusions In conclusion, Hcy impaired autophagy in VSMCs, followed by up-regulated ETB receptor through AMPK/mTOR signaling pathway (Fig. 8). It may provide new therapeutic targets for treatment of Hcy-induced CVDs.
    Conflict of interest
    Acknowledgment This work was supported by the National Natural Science Foundation of China (81500350), the Supporting Fund Project of Xi'an Medical University (2016PT27), the Key Scientific Research Plan Project of Education Department of Shaanxi Province (16JS098).
    Enhanced sodium transport in the renal proximal tubule and thick ascending limb of Henle occurs in human essential and rodent genetic hypertension, , . This enhanced sodium transport may be caused by increased activity of antinatriuretic agents and/or decreased activity of natriuretic agents, , , , , . The renin-angiotensin system plays a critical role in the regulation of blood pressure and renal excretory function, , . Angiotensin II is functionally the most relevant peptide of this system, and its antinatriuretic and prohypertensive actions are mediated by the activation of the angiotensin II type 1 (AT) receptor, , , . Endothelins are a family of three isopeptides (ET1, ET2, and ET3), for which at least two types of receptors have been identified (ETA and ETB),. Renal proximal tubules express AT, ETA, and ETB receptors, , , , . Several studies have shown that the ETA receptor decreases while the ETB receptor increases sodium excretion, , , , , . The interplay between the natriuretic ETB/antinatriuretic ETA and AT receptors represents one pathway in the regulation of renal sodium and water excretion, , . The renin-angiotensin system may exert some of its effects via an interaction with the endothelin system, , . Angiotensin II regulates endothelin synthesis in the kidney. Endothelin has multifaceted effects on the renin-angiotensin-aldosterone system, such as a dose-dependent inhibition of renin production and direct stimulation of aldosterone and promotion of growth of the adrenal cortex, , , .