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Role of opioid signaling in kidney damage during the development of salt-induced hypertension.
Life Science Alliance ( IF 3.3 ) Pub Date : 2020-10-12 , DOI: 10.26508/lsa.202000853
Daria Golosova 1 , Oleg Palygin 1, 2 , Ruslan Bohovyk 1 , Christine A Klemens 1 , Vladislav Levchenko 1 , Denisha R Spires 1 , Elena Isaeva 1 , Ashraf El-Meanawy 2, 3 , Alexander Staruschenko 2, 4, 5
Affiliation  

Opioid use is associated with predictors of poor cardiorenal outcomes. However, little is known about the direct impact of opioids on podocytes and renal function, especially in the context of hypertension and CKD. We hypothesize that stimulation of opioid receptors (ORs) contributes to dysregulation of intracellular calcium ([Ca2+]i) homeostasis in podocytes, thus aggravating the development of renal damage in hypertensive conditions. Herein, freshly isolated glomeruli from Dahl salt-sensitive (SS) rats and human kidneys, as well as immortalized human podocytes, were used to elucidate the contribution of specific ORs to calcium influx. Stimulation of κ-ORs, but not μ-ORs or δ-ORs, evoked a [Ca2+]i transient in podocytes, potentially through the activation of TRPC6 channels. κ-OR agonist BRL52537 was used to assess the long-term effect in SS rats fed a high-salt diet. Hypertensive rats chronically treated with BRL52537 exhibited [Ca2+]i overload in podocytes, nephrinuria, albuminuria, changes in electrolyte balance, and augmented blood pressure. These data demonstrate that the κ-OR/TRPC6 signaling directly influences podocyte calcium handling, provoking the development of kidney injury in the opioid-treated hypertensive cohort.

中文翻译:

阿片样物质信号传导在盐性高血压发展过程中肾损伤中的作用。

阿片类药物的使用与不良心肾结果的预测因素有关。然而,关于阿片类药物对足细胞和肾功能的直接影响知之甚少,尤其是在高血压和 CKD 的情况下。我们假设阿片受体 (ORs) 的刺激会导致足细胞中细胞内钙 ([Ca 2+ ] i ) 稳态的失调,从而加剧高血压疾病中肾损伤的发展。在此,使用来自达尔盐敏感性 (SS) 大鼠和人类肾脏以及永生化人类足细胞的新鲜分离的肾小球来阐明特定 OR 对钙内流的贡献。刺激 κ-ORs,但不是 μ-ORs 或 δ-ORs,诱发 [Ca 2+ ] i足细胞中的短暂性,可能通过激活 TRPC6 通道。κ-OR 激动剂 BRL52537 用于评估喂食高盐饮食的 SS 大鼠的长期影响。用 BRL52537 长期治疗的高血压大鼠表现出足细胞 [Ca 2+ ] i超载、肾尿、白蛋白尿、电解质平衡变化和血压升高。这些数据表明,κ-OR/TRPC6 信号传导直接影响足细胞钙处理,从而在阿片类药物治疗的高血压组中引发肾损伤。
更新日期:2020-10-20
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