Furusho Taisuke, Sohara Eisei, Mandai Shintaro, Kikuchi Hiroaki, Takahashi Naohiro, Fujimaru Takuya, Hashimoto Hiroko, Arai Yohei, Ando Fumiaki, Zeniya Moko, Mori Takayasu, Susa Koichiro, Isobe Kiyoshi, Nomura Naohiro, Yamamoto Kohei, Okado Tomokazu, Rai Tatemitsu, Uchida Shinichi
Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
Kidney Int. 2020 Apr;97(4):713-727. doi: 10.1016/j.kint.2019.11.021. Epub 2020 Feb 11.
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.
无赖氨酸激酶（WNK）-STE20/SPS1相关富含脯氨酸/丙氨酸激酶（SPAK）-氯化钠共转运体（NCC）磷酸化级联的不适当过度激活会增加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病因，但WNK磷酸化级联的参与情况尚不清楚。此外，尽管免疫系统对盐敏感性很重要，但尚未研究其对WNK激酶的影响。在此，我们证明在CKD的马兜铃酸肾病小鼠模型中，远端曲管中WNK1而非WNK4的蛋白丰度增加。相应地，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WNK1-SPAK-NCC磷酸化级联的激活，导致盐敏感性高血压。在CKD的腺嘌呤肾病模型中WNK1也增加，但在肾大部切除模型中未增加。通过比较这三种模型中关注免疫系统的转录本，我们推测肿瘤坏死因子（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端曲管中NEDD4-2表达的降低和WNK1-SPAK-NCC磷酸化级联的上调。因此，CKD中盐敏感性高血压是通过TNF-α激活肾脏WNK1-SPAK-NCC磷酸化级联诱导的，这反映了与免疫系统的联系。
