肾血管性高血压(RVHT)的特征是肾动脉狭窄和肾素-血管紧张素系统(RAS)过度活化。Apelin,以RAS的负调制而闻名,对心血管疾病有保护作用。apelin的主要活性形式的作用和机制,RVHT中的Apelin-13尚不清楚。在这项研究中,雄性Sprague-Dawley大鼠分为对照组,2K1C型号,和2K1C与apelin-13治疗组。使用免疫组织化学和分子技术分析肾素表达。通过蛋白质印迹法评估全长(前)肾素受体(fPRR)和可溶性PRR(sPRR)水平,和cAMP水平使用ELISA测量。血浆肾素含量,血浆肾素活性(PRA),血管紧张素II(AngII),和sPRR水平通过ELISA测定。人Calu-6和小鼠As4.1细胞用于研究肾素产生机制。2K1C模型显示收缩压(SBP)升高,血浆肾素含量,PRA,sPRR,和AngII水平,而apelin-13治疗降低了这些升高。Apelin-13抑制cAMP的产生,肾素mRNA表达,蛋白质合成,和肾组织中PRR/sPRR蛋白的表达。在Calu-6细胞中,cAMP诱导的fPRR和位点1蛋白酶(S1P)衍生的sPRR表达,被CREB抑制阻断。Apelin-13抑制cAMP升高,CREB磷酸化,fPRR/sPRR蛋白表达,和肾素生产。重组sPRR(sPRR-His)刺激肾素产生,被PRR诱骗肽PRO20和S1P抑制剂PF429242抑制。这些发现提示apelin-13通过cAMP/PKA/sPRR通路抑制血浆肾素表达,为RVHT提供了一种潜在的治疗方法。了解肾素产生的调节对于开发有效的治疗方法至关重要。
Renovascular hypertension (RVHT) is characterized by renal artery stenosis and overactivated renin-angiotensin system (RAS). Apelin, known for its negative modulation of RAS, has protective effects against cardiovascular diseases. The role and mechanisms of the primary active form of apelin, apelin-13, in RVHT are unclear. In this study, male Sprague-Dawley rats were divided into control, two-kidney one-clip (2K1C) model, and 2K1C with apelin-13 treatment groups. Renin expression was analyzed using immunohistochemistry and molecular techniques. Full-length (pro)renin receptor (fPRR) and soluble PRR (sPRR) levels were assessed via Western blotting, and cAMP levels were measured using ELISA. Plasma renin content, plasma renin activity (PRA), angiotensin II (ANG II), and sPRR levels were determined by ELISA. Human Calu-6 and mouse As4.1 cells were used to investigate renin production mechanisms. The 2K1C model exhibited increased systolic blood pressure, plasma renin content, PRA, sPRR, and ANG II levels, while apelin-13 treatment reduced these elevations. Apelin-13 inhibited cAMP production, renin mRNA expression, protein synthesis, and PRR/sPRR protein expression in renal tissue. In Calu-6 cells, cAMP-induced fPRR and site-1 protease (S1P)-derived sPRR expression, which was blocked by cAMP-responsive element-binding protein (CREB) inhibition. Apelin-13 suppressed cAMP elevation, CREB phosphorylation, fPRR/sPRR protein expression, and renin production. Recombinant sPRR (sPRR-His) stimulated renin production, which was inhibited by the PRR decoy peptide PRO20 and S1P inhibitor PF429242. These findings suggest that apelin-13 inhibits plasma renin expression through the cAMP/PKA/sPRR pathway, providing a potential therapeutic approach for RVHT. Understanding the regulation of renin production is crucial for developing effective treatments.NEW & NOTEWORTHY Our research elucidated that apelin-13 inhibits renin production through the cAMP/PKA/soluble (pro)renin receptor pathway, presenting a promising therapeutic approach for renovascular hypertension (RVHT) by targeting renin expression mechanisms. These findings underscore the potential of apelin-13 as a novel strategy to address RVHT.