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 salt-sensitive 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)-α regulates WNK1 protein expression. In fact, TNF-α 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-α 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-α, reflecting a link with the immune system.

中文翻译：

---

肾脏 TNFα 激活 WNK 磷酸化级联反应并导致慢性肾病中的盐敏感性高血压。

无赖氨酸激酶 (WNK)-STE20/SPS1 相关脯氨酸/富含丙氨酸激酶 (SPAK)-氯化钠协同转运蛋白 (NCC) 磷酸化级联反应的不当过度激活会增加远端肾肾单位的钠重吸收，导致盐敏感性高血压。虽然慢性肾病 (CKD) 是盐敏感高血压的常见原因，但 WNK 磷酸化级联反应的参与尚不清楚。此外，尽管免疫系统对盐敏感性很重要，但尚未研究免疫系统对 WNK 激酶的影响。在这里，我们证明了在马兜铃酸肾病 CKD 小鼠模型的远曲小管中，WNK1 的蛋白质丰度增加，但 WNK4 的蛋白质丰度没有增加。因此，SPAK 和 NCC 的磷酸化也增加。而且，在该模型中，高盐饮食不能充分抑制 WNK1-SPAK-NCC 磷酸化级联反应的激活，导致盐敏感性高血压。WNK1 在腺嘌呤肾病中也增加，但在次全肾切除术、CKD 模型中没有增加。通过比较这三种专注于免疫系统的模型的转录本，我们假设肿瘤坏死因子 (TNF)-α 调节 WNK1 蛋白表达。事实上，TNF-α 通过降低降解 WNK1 蛋白的 NEDD4-2 E3-连接酶的转录和蛋白水平，增加了培养的肾小管细胞中 WNK1 蛋白的表达。此外，TNF-α抑制剂依那西普在马兜铃酸肾病模型中逆转了体内远曲小管中NEDD4-2表达的减少和WNK1-SPAK-NCC磷酸化级联反应的上调。因此，