The (pro)renin receptor ((P)RR), which is a recently discovered molecule of the renin-angiotensin system, plays an important role in the development of cardiovascular diseases. However, the molecular properties and the subcellular distribution of (P)RR remain controversial. In this study, (P)RR-Venus in Chinese hamster ovary (CHO) cells ((P)RR-Venus-CHO) or endogenous (P)RR in human vascular smooth muscle cells (VSMC) were constitutively cleaved without any stimulation, and secretion of the aminoterminal fragment (NTF-(P)RR) into the media was determined using western blot analysis. Immunofluorescent analysis showed robust expression of (P)RR in the endoplasmic reticulum (ER) or the Golgi but not in the plasma membrane. Moreover, we identified ADAM19, which is expressed in the Golgi, as one of cleaving proteases of (P)RR. Transfected ADAM19 evoked the shedding of (P)RR, whereas transfected dominant negative ADAM19 suppressed it. Although (P)RR contains a furin cleavage site, neither the furin-deficient LoVo cells nor furin inhibitor-treated VSMC lost NTF-(P)RR in the media. The secreted NTF-(P)RR induced the renin activity of prorenin in the extracellular space. We describe that (P)RR is mainly localized in the subcellular organelles, such as the ER and Golgi, and (P)RR is cleaved by ADAM19 in the Golgi resulting in two fragments, NTF-(P)RR and CTF-(P)RR. These results may suggest that (P)RR is predominantly secreted into the extracellular space. Hypertension Research (2011) 34, 599-605; doi:10.1038/hr.2010.284; published online 27 January 2011Keywords: ADAM19; ectodomain shedding; (pro)renin receptor; renin-angiotensin system INTRODUCTION The (pro)renin receptor ((P)RR) is a recently discovered molecule of the renin-angiotensin system (RAS), which plays pivotal roles in the regulation of the cardiovascular system under normal and pathological conditions. (P)RR binds both renin and prorenin, which is the precursor form of renin. 1 Although the binding of renin to (P)RR may increase its catalytic activity, the binding affinity between (P)RR and renin is lower than that of (P)RR and prorenin. These results indicate that it may be necessary to focus on the interaction between (P)RR and prorenin. Prorenin does not display protease activity in the plasma because the enzymatic cleft is covered by the prosegment. 2 However, the binding of prorenin to (P)RR evokes the renin activity without removal of its prosegment. This nonproteolytic activation of prorenin contributes to the activation of the local RAS. In addition to the enzymatic activity, renin/prorenin has been shown to provide other (P)RR-mediated effects. 3 The binding of renin/prorenin to (P)RR induces the activation of intracellular signaling, including the p38 MAP kinase-HSP27 cascade, the PI3K pathway and the ERK 1/2 pathway; these effects occur independently of angiotensin II, which is a final product of RAS. 2,4,5 Although this evidence strongly supports (P)RR localization in the plasma membrane, the subcellular localization of (P)RR remains unknown. (P)R...
Brain-derived neurotrophic factor (BDNF) regulates the survival and growth of neurons, and influences synaptic efficiency and plasticity. Peripheral BDNF levels in patients with schizophrenia have been widely reported in the literature. However, it is still controversial whether peripheral levels of BDNF are altered in patients with schizophrenia. The peripheral BDNF levels previously reported in patients with schizophrenia were total BDNF (proBDNF and mature BDNF) as it was unable to specifically measure mature BDNF due to limited BDNF antibody specificity. In this study, we examined whether peripheral levels of mature BDNF were altered in patients with treatment-resistant schizophrenia. Matrix metalloproteinase-9 (MMP-9) levels were also measured, as MMP-9 plays a role in the conversion of proBDNF to mature BDNF. Twenty-two patients with treatment-resistant schizophrenia treated with clozapine and 22 age- and sex-matched healthy controls were enrolled. The plasma levels of mature BDNF and MMP-9 were measured using ELISA kits. No significant difference was observed for mature BDNF however, MMP-9 was significantly increased in patients with schizophrenia. The significant correlation was observed between mature BDNF and MMP-9 plasma levels. Neither mature BDNF nor MMP-9 plasma levels were associated clinical variables. Our results do not support the view that peripheral BDNF levels are associated with schizophrenia. MMP-9 may play a role in the pathophysiology of schizophrenia and serve as a biomarker for schizophrenia.
inducible kinase 2 (SIK2) is expressed abundantly in adipose tissues and represses cAMP-response element-binding protein (CREB)-mediated gene expression by phosphorylating the coactivator transducer of regulated CREB activity (TORC2). Phosphorylation at Ser 587 of SIK2 diminishes its TORC2 phosphorylation activity. In 3T3-L1 white adipocytes, SIK2 downregulates lipogenic gene in response to nutritional stresses. To investigate the impact of SIK2 on the function of brown adipose tissue (BAT), we used T37i brown adipocytes, mice with diet-induced obesity, and SIK2 mutant (S587A) transgenic mice. When T37i adipocytes were treated with insulin, the levels of peroxisome proliferator-activated receptor-coactivator-1␣ (PGC-1␣) and uncoupling protein-1 (UCP-1) mRNA were increased, and the induction was inhibited by overexpression of SIK2 (S587A) mutant or dominant-negative CREB. Insulin enhanced SIK2 phosphorylation at Ser 587 , which was accompanied by decrease in phospho-TORC2. Similarly, the decrease in the level of SIK2 phosphorylation at Ser 587 was observed in the BAT of mice with diet-induced obesity, which was negatively correlated with TORC2 phosphorylation. To confirm the negative correlation between SIK2 phosphorylation at Ser 587 and TORC2 phosphorylation in BAT, SIK2 mutant (S587A) was overexpressed in adipose tissues by using the adipocyte fatty acid-binding protein 2 promoter. The expression of recombinant SIK2 (S587A) was restricted to BAT, and the levels of phospho-TORC2 were elevated in BAT of transgenic mice. Male transgenic mice developed high-fat diet-induced obesity, and their BAT expressed low levels of PGC-1␣
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