PDF(Pubmed)
Abstract：
Atrial Natriuretic Peptide (ANP) plays an important role in blood pressure regulation. Low levels of ANP correlate with the development of salt-sensitive hypertension (SS-HTN). Our previous studies indicated that ANP deficiency exacerbated renal function decline in SS-HTN. In the heart and fat tissue, ANP was reported to affect lipid peroxidation and mitochondrial bioenergetics but the effects of ANP on mitochondrial function in the kidney are unexplored. We hypothesized that ANP deficiency in SS-HTN causes renal bioenergetic shift, leading to disruption of mitochondrial network and oxidative stress. To address the hypothesis, we placed Dahl SS wild-type (SSWT) and ANP knockout (SSNPPA-/-) rats on 4% NaCl high salt (HS) diet to induce HTN or maintained them on 0.4% NaCl normal salt (NS) diet and assessed mitochondrial bioenergetics and dynamics using spectrofluorimetry, Seahorse assay, electron paramagnetic resonance (EPR) spectroscopy, Western blotting, electron microscopy, PCR and cytokine assays. We report that under high salt conditions, associated with hypertension and renal damage, the SSNPPA-/- rats exhibit a decrease in mitochondrial membrane potential and elevation in mitochondrial ROS levels compared to SSWT. The redox shift is also evident by the presence of more pronounced medullar lipid peroxidation in the SSNPPA-/- strain. We also revealed fragmented, more damaged mitochondria in the SSNPPA-/- rats, accompanied by increased turnover and biogenesis. Overall, our data indicate that ANP deficiency causes disruptions in mitochondrial bioenergetics and dynamics which likely contributes to aggravation of the renal damage and hypertension in the Dahl SS rat; the major pathological effects are evident in the groups subjected to a combined salt and ANP deficiency-induced mitochondrial stress.
摘要：
心房利钠肽(ANP)在血压调节中起重要作用。低水平的ANP与盐敏感性高血压（SS-HTN）的发展有关。我们先前的研究表明，ANP缺乏会加剧SS-HTN的肾功能下降。在心脏和脂肪组织中，据报道，ANP会影响脂质过氧化和线粒体生物能学，但尚未研究ANP对肾脏线粒体功能的影响。我们假设SS-HTN中的ANP缺乏会导致肾脏生物能量转移，导致线粒体网络破坏和氧化应激。为了解决这个假设，我们将DahlSS野生型（SSWT）和ANP敲除（SSNPPA-/-）大鼠置于4％NaCl高盐（HS）饮食中，以诱导HTN或将其维持在0.4％NaCl常盐（NS）饮食中，并使用荧光光谱法评估线粒体生物能学和动力学，海马试验,电子顺磁共振(EPR)光谱,西方印迹,电子显微镜，PCR和细胞因子测定。我们报告说，在高盐条件下，与高血压和肾损害有关，与SSWT相比，SSNPPA-/-大鼠表现出线粒体膜电位降低和线粒体ROS水平升高。通过SSNPPA-/-菌株中更明显的髓质脂质过氧化的存在，氧化还原的变化也很明显。我们还揭示了支离破碎，SSNPPA-/-大鼠线粒体受损更多，伴随着营业额和生物发生的增加。总的来说,我们的数据表明,ANP缺乏会导致线粒体生物能学和动力学的破坏,这可能导致DahlSS大鼠肾脏损害和高血压的加重;主要病理效应在盐和ANP缺乏联合诱导的线粒体应激组明显.
