Department of Nephrology, Huadong Hospital Affiliated to Fudan University, Shanghai, PR China; Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai, PR China.
Department of Traditional Chinese Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai, PR China; Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai, PR China.
Eur J Pharmacol. 2022 Oct 15;932:175237. doi: 10.1016/j.ejphar.2022.175237. Epub 2022 Sep 2.
Increasing evidence indicates that hyperuricaemia (HUA) is not only a result of decreased renal urate excretion but also a contributor to kidney disease. Na-K-ATPase (NKA), which establishes the sodium gradient for urate transport in proximal tubular epithelial cells (PTECs), its impairment leads to HUA-induced nephropathy. However, the specific mechanism underlying NKA impairment-mediated renal tubular injury and increased urate reabsorption in HUA is not well understood. In this study, we investigated whether autophagy plays a key role in the NKA impairment signalling and increased urate reabsorption in HUA-induced renal tubular injury. Protein spectrum analysis of exosomes from the urine of HUA patients revealed the activation of lysosomal processes, and exosomal expression of lysosomal-associated membrane protein-2 was associated with increased serum levels and decreased renal urate excretion in patients. We demonstrated that high uric acid (UA) induced lysosome dysfunction, autophagy and inflammation in a time- and dose-dependent manner and that high UA and/or NKA α1 siRNA significantly increased mitochondrial abnormalities, such as reductions in mitochondrial respiratory complexes and cellular ATP levels, accompanied by increased apoptosis in cultured PTECs. The autophagy inhibitor hydroxychloroquine (HCQ) ameliorated NKA impairment-mediated mitochondrial dysfunction, Nod-like receptor pyrin domain-containing protein 3 (NLRP3)-interleukin-1β (IL-1β) production, and abnormal urate reabsorption in PTECs stimulated with high UA and in rats with oxonic acid (OA)-induced HUA. Our findings suggest that autophagy plays a pivotal role in NKA impairment-mediated signalling and abnormal urate reabsorption in HUA-induced renal tubular injury and that inhibition of autophagy by HCQ could be a promising treatment for HUA.
越来越多的证据表明，高尿酸血症（HUA）不仅是肾脏尿酸排泄减少的结果，也是导致肾脏疾病的原因之一。钠钾-ATP 酶（NKA）在近端肾小管上皮细胞（PTEC）中建立尿酸转运的钠离子梯度，其功能障碍导致 HUA 引起的肾病。然而，NKA 功能障碍介导的肾小管损伤和 HUA 中尿酸重吸收增加的具体机制尚不清楚。在这项研究中，我们研究了自噬是否在 NKA 功能障碍信号和 HUA 引起的肾小管损伤中尿酸重吸收增加中起关键作用。HUA 患者尿液外泌体的蛋白质谱分析显示溶酶体过程被激活，并且溶酶体相关膜蛋白-2 的外泌体表达与患者血清水平升高和肾脏尿酸排泄减少有关。我们证明，高尿酸（UA）以时间和剂量依赖的方式诱导溶酶体功能障碍、自噬和炎症，并且高 UA 和/或 NKAα1 siRNA 显著增加线粒体异常，如线粒体呼吸复合物减少和细胞 ATP 水平降低，同时培养的 PTEC 中凋亡增加。自噬抑制剂羟氯喹（HCQ）改善了 NKA 功能障碍介导的线粒体功能障碍、Nod 样受体吡喃结构域包含蛋白 3（NLRP3）-白细胞介素 1β（IL-1β）产生以及高 UA 刺激的 PTEC 中和草酸（OA）诱导的 HUA 大鼠中异常的尿酸重吸收。我们的研究结果表明，自噬在 NKA 功能障碍介导的信号和 HUA 引起的肾小管损伤中尿酸重吸收异常中起关键作用，并且 HCQ 抑制自噬可能是治疗 HUA 的一种有前途的方法。
