Renal TNFα activates the WNK phosphorylation cascade and contributes to salt-sensitive hypertension in chronic kidney disease
Renal TNFα activates the WNK phosphorylation cascade and contributes to salt-sensitive hypertension in chronic kidney disease
复制标题
DOI：
10.1016/j.kint.2019.11.021
复制
发表时间：
2020-04-01
影响因子：
19.6
通讯作者：
Uchida, Shinichi
中科院分区：
文献类型：
--
作者：
Furusho, Taisuke;Sohara, Eisei;Uchida, Shinichi
无赖氨酸激酶（WNK）-STE 20/SPS 1相关的脯氨酸/丙氨酸丰富激酶（SPAK）-氯化钠协同转运蛋白（NCC）磷酸化级联的不适当过度激活增加了远端肾单位的钠重吸收，导致盐敏感性高血压。虽然慢性肾脏病（CKD）是盐敏感性高血压的常见原因，但WNK磷酸化级联反应的参与尚不清楚。此外，免疫系统对WNK激酶的影响尚未研究，尽管免疫系统对盐敏感性很重要。在这里，我们证明了WNK 1，但不是WNK 4的蛋白丰度，在CKD马兜铃酸肾病小鼠模型的远曲小管增加。因此，SPAK和NCC的磷酸化也增加。此外，在该模型中，高盐饮食不能充分抑制WNK 1-SPAK-NCC磷酸化级联反应的激活，导致盐敏感性高血压。WNK 1在腺嘌呤肾病中也增加，但在CKD的肾大部切除模型中不增加。通过比较这三种模型的转录本，我们假设肿瘤坏死因子（TNF）-α调节WNK 1蛋白的表达。事实上，TNF-α通过降低降解WNK 1蛋白的NEDD 4 -2 E3-连接酶的转录和蛋白水平来增加培养的肾小管细胞中的WNK 1蛋白表达。此外，在马兜铃酸肾病模型中，TNF-α抑制剂依那西普逆转了体内远曲小管中NEDD 4 -2表达的降低和WNK 1-SPAK-NCC磷酸化级联反应的上调。因此，盐敏感性高血压是通过TNF-α激活肾脏WNK 1-SPAK-NCC磷酸化级联反应诱导的，反映了与免疫系统的联系。
The inappropriate over-activation of the with-no-lysine kinase (WNK)-STE20/SPS1-related proline/alanine-rich kinase (SPAK)-sodium chloride cotransporter (NCC) phosphorylation cascade increases sodium reabsorption in distal kidney nephrons, resulting in salt-sensitive hypertension. Although chronic kidney disease (CKD) is a common cause of salt-sensitive hypertension, the involvement of the WNK phosphorylation cascade is unknown. Moreover, the effect of immune systems on WNK kinases has not been investigated despite the fact that immune systems are important for salt sensitivity. Here we demonstrate that the protein abundance of WNK1, but not of WNK4, was increased at the distal convoluted tubules in the aristolochic acid nephropathy mouse model of CKD. Accordingly, the phosphorylation of both SPAK and NCC was also increased. Moreover, a high-salt diet did not adequately suppress activation of the WNK1-SPAK-NCC phosphorylation cascade in this model, leading to saltsensitive hypertension. WNK1 also was increased in adenine nephropathy, but not in subtotal nephrectomy, models of CKD. By comparing the transcripts of these three models focusing on immune systems, we hypothesized that tumor necrosis factor (TNF)-alpha regulates WNK1 protein expression. In fact, TNF-alpha increased WNK1 protein expression in cultured renal tubular cells by reducing the transcription and protein levels of NEDD4-2 E3-ligase, which degrades WNK1 protein. Furthermore, the TNF-alpha inhibitor etanercept reversed the reduction of NEDD4-2 expression and upregulation of the WNK1-SPAK-NCC phosphorylation cascade in distal convoluted tubules in vivo in the aristolochic acid nephropathy model. Thus, salt-sensitive hypertension is induced in CKD via activation of the renal WNK1- SPAK-NCC phosphorylation cascade by TNF-alpha, reflecting a link with the immune system.