Post-injury Inhibition of Endothelin-1 Dependent Renal Vasoregulation Mitigates Rhabdomyolysis-Induced Acute Kidney Injury.
Post-injury Inhibition of Endothelin-1 Dependent Renal Vasoregulation Mitigates Rhabdomyolysis-Induced Acute Kidney Injury.
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DOI：
10.1093/function/zqad022
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发表时间：
2023
期刊：
影响因子：
6.2
通讯作者：
Adebiyi, Adebowale
中科院分区：
文献类型：
--
作者：
Afolabi, Jeremiah M.;Kanthakumar, Praghalathan;Williams, Jada D.;Kumar, Ravi;Soni, Hitesh;Adebiyi, Adebowale
在横纹肌溶解症患者中，肌红蛋白大量释放到循环中是肾损伤的主要原因。肌红蛋白可导致直接肾损伤和严重的肾血管收缩。肾血管阻力（RVR）的增加导致肾血流量（RBF）和肾小球滤过率（GFR）降低、肾小管损伤和急性肾损伤（阿基）。横纹肌溶解诱导阿基的机制尚未完全了解，但可能涉及肾脏局部产生血管活性介质。研究表明，肌红蛋白刺激肾小球系膜细胞产生内皮素-1（ET-1）。在甘油诱导的横纹肌溶解大鼠中，循环ET-1也增加。然而，在横纹肌溶解诱导的阿基中，ET-1产生的上游机制和ET-1作用的下游效应物仍不清楚。血管活性ET-1是由ET转换酶1（ECE-1）诱导的无活性大ET蛋白水解加工成生物活性肽而产生的。ET-1诱导的血管调节的下游离子通道效应物包括瞬时受体电位阳离子通道，亚家族C成员3（TRPC 3）。这项研究表明，在Wistar大鼠中，甘油诱导的横纹肌溶解促进ECE-1依赖性ET-1产生、RVR增加、GFR降低和阿基。通过损伤后药物抑制ECE-1、ET受体和TRPC 3通道，可减弱横纹肌溶解诱导的大鼠RVR和阿基增加。CRISPR/Cas9介导的TRPC 3通道敲除减弱了ET-1诱导的肾血管反应性和横纹肌溶解诱导的阿基。这些发现表明ECE-1驱动的ET-1产生和下游TRPC 3依赖性肾血管收缩的激活有助于横纹肌溶解诱导的阿基。因此，损伤后抑制ET-1介导的肾血管调节可能为横纹肌溶解诱导的阿基提供治疗靶点。
In patients with rhabdomyolysis, the overwhelming release of myoglobin into the circulation is the primary cause of kidney injury. Myoglobin causes direct kidney injury as well as severe renal vasoconstriction. An increase in renal vascular resistance (RVR) results in renal blood flow (RBF) and glomerular filtration rate (GFR) reduction, tubular injury, and acute kidney injury (AKI). The mechanisms that underlie rhabdomyolysis-induced AKI are not fully understood but may involve the local production of vasoactive mediators in the kidney. Studies have shown that myoglobin stimulates endothelin-1 (ET-1) production in glomerular mesangial cells. Circulating ET-1 is also increased in rats subjected to glycerol-induced rhabdomyolysis. However, the upstream mechanisms of ET-1 production and downstream effectors of ET-1 actions in rhabdomyolysis-induced AKI remain unclear. Vasoactive ET-1 is generated by ET converting enzyme 1 (ECE-1)-induced proteolytic processing of inactive big ET to biologically active peptides. The downstream ion channel effectors of ET-1-induced vasoregulation include the transient receptor potential cation channel, subfamily C member 3 (TRPC3). This study demonstrates that glycerol-induced rhabdomyolysis in Wistar rats promotes ECE-1-dependent ET-1 production, RVR increase, GFR decrease, and AKI. Rhabdomyolysis-induced increases in RVR and AKI in the rats were attenuated by post-injury pharmacological inhibition of ECE-1, ET receptors, and TRPC3 channels. CRISPR/Cas9-mediated knockout of TRPC3 channels attenuated ET-1-induced renal vascular reactivity and rhabdomyolysis-induced AKI. These findings suggest that ECE-1-driven ET-1 production and downstream activation of TRPC3-dependent renal vasoconstriction contribute to rhabdomyolysis-induced AKI. Hence, post-injury inhibition of ET-1-mediated renal vasoregulation may provide therapeutic targets for rhabdomyolysis-induced AKI.
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影响因子：
3.3
作者：
Hill, NS;Warburton, RR;Klinger, JR
通讯作者：
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影响因子：
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DOI：
10.1152/ajprenal.00338.2003
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