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    • Coincident with APJ receptor several cell

    2023-12-26

    Coincident with APJ receptor, several cell types in the body can synthesize apelin protein. For example, the highest apelin concentrations in the body have been found in the rat central nervous system, pituitary gland, lungs, cardiac muscle, gastrointestinal tract and mammary glands, with lower values in kidneys and skeletal muscles [12,13]. In the rat gastrointestinal tract, the highest apelin concentrations have been found in both gastric exocrine and endocrine cells, in the fundus part of the stomach (in the mucous neck, parietal and chief cells) and in the proximal part of the small intestine. It is worth noting that the apelin concentration decreases along the small intestine to the colon [[14], [15], [16]]. In human, mouse, rat, pig and cat pancreas islets, apelin is expressed in alpha, beta and PP cells [17]. Also, apelin is found in serum, colostrum and mature milk [18]. During pregnancy and lactation, breast apelin expression can increase from ~7 to 20 times [19]. It is also known that apelin is secreted by adipose tissue, and in obese individuals suffering from hyperinsulinaemia, it is produced in excessive amounts [20]. The apelin action in the organism is multidirectional and depends on the dose and route of administration. For example, intracerebroventricular (i.c.v.) apelin administration increases water uptake, alzheimer's disease and corticosterone hormone secretion in a dose-dependent manner but decreases prolactin, thyroid-stimulating hormone (TSH) and growth hormone secretion [21,22]. Apelin also stimulates the secretion of hypothalamic-releasing hormones (corticotropin-releasing hormone and vasopressin hormone) [21]. In rats, intravenous apelin injection causes immediate reduction of the blood pressure, whereas its intraperitoneal (i.p.) administration increases water uptake [23]. A protective action of apelin on cardiac muscle cells as well as its active participation in angiogenesis have also been reported [24,25]. Apelin also stimulates proliferation and inhibits apoptosis of the mouse and human osteoblasts [26]. Thus, it can be stated that apelin may be involved in several physiological processes occurring in the organism and can potentially be used as a therapeutic drug in many diseases and pathologies. Therefore, the aim of this article is to present the newest knowledge on the role of the apelin/APJ system in various diseases.
    Methods To collect needed information, databases such as PubMed (www.ncbi.nlm.nih.gov/pubmed/), Scopus (www.scopus.com/) and Google Scholar (https://scholar.google.com/) were searched. Mainly, the articles published in the last decade (up to February 2018) were used. Search terms included “the role of apelin in: neurological, metabolic, hypertension, respiratory, gastrointestinal, hepatic, kidney and cancer diseases”.
    The role of apelin in neurological disorders The apelin/APJ system plays an important role in the pathogenesis of mental disorders and also in pain modulation (Table 1) [[27], [28], [29]]. Expression of apelin and APJ has been found in pain-related structures, including the dorsal root ganglia, spinal cord, periaqueductal grey, and dorsal raphe nucleus, and is thus thought to take part in nociception [28]. It has been demonstrated that the apelin/APJ system may act as an analgesic, and specifically, apelin-13 may exert inhibitory effects on inflammatory pain. For example, in rats suffering from inflammatory pain caused by intraplantar injection of complete Freund's adjuvant (CFA), a decrease in the expression of endogenous apelin in the spinal cord is observed, whereas the normalization of apelin/APJ synthesis in the rat spinal cord using electroacupuncture reduces the pain [28,29]. The spinal apelin/APJ system is also activated during nerve injury and can be involved in neuropathic pain initiation and maintenance. Inhibition of apelin receptor APJ reduces mechanical allodynia and heat hyperalgesia. However, an intrathecal injection of apelin-13 at a dose of 10 μg exerts no effect on pain behaviour [30]. In rats with neuropathic pain caused by spinal cord injury, the intrathecal administration of (Pyr1)-apelin-13 for alleviating mechanical allodynia increases thermal paw withdrawal latency and reduces apoptosis. Thus, the beneficial effects of (Pyr1)-apelin-13 on neuropathic pain and locomotion are confirmed [31]. Also, apelin-13 has protective properties against pentylenetetrazole (PTZ)-induced toxicity in rat brain primary culture. Kalantaripour et al. [32] have noticed that apelin-13 incubated in primary cortical cells prevents PTZ-induced cell toxicity, decreases expression of inflammatory mediators, the level of intracellular calcium [Ca++] and caspase-3 expression without toxic effects on these cells [32]. The neuroprotective effect of apelin has also been noticed during secondary injury after traumatic brain injury and in mice suffering from intracerebral haemorrhage. In mice, administration of apelin-13 improves motor performance, decreases aquaporin-4 expression, mitigates blood-brain barrier destruction, decreases cerebral water content, and reduces caspase-3 and Bax expression in the cerebral cortex and hippocampus [33,34]. Similarly, chronic normobaric hypoxia decreases APJ expression in the mouse hippocampus. Treatment of mice suffering from chronic normobaric hypoxia (CHN) with apelin-13 (20 nmol/kg/d, i.p.) for 4 weeks increases APJ and p-CAMKII expression but decreases Iba-1 and NF-κB expression in the hippocampus. Thus, it can be suggested that apelin may ameliorate CNH-induced anxiety-like behaviour [35]. Scientific studies confirm the presence of apelin and its receptor in nervous tissues (ventral horn and area around the central canal, glial cells in the neurons of the ventral horn, choline acetyltransferase (ChAT)-positive cells) [27]. Also, in an amyotrophic lateral sclerosis mouse model (SOD1G93A mice), a lowered apelin expression in spinal cord, declining along with the progression of amyotrophic lateral sclerosis, is observed. According to Kasai et al. [27], it can be stated that involvement of endogenous apelin in the pathogenesis of amyotrophic lateral sclerosis is a fact and that the apelin/APJ system in the spinal cord may have a neuroprotective effect on this process.