Renal TNFα activates the WNK phosphorylation cascade and contributes to salt-sensitive hypertension in chronic kidney disease
| Autor: | Shintaro Mandai, Kohei Yamamoto, Hiroaki Kikuchi, Fumiaki Ando, Koichiro Susa, Tomokazu Okado, Naohiro Takahashi, Moko Zeniya, Naohiro Nomura, Takayasu Mori, Shinichi Uchida, Yohei Arai, Takuya Fujimaru, Kiyoshi Isobe, Eisei Sohara, Taisuke Furusho, Hiroko Hashimoto, Tatemitsu Rai |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty 030232 urology & nephrology Protein Serine-Threonine Kinases Nephropathy Phosphorylation cascade 03 medical and health sciences Mice 0302 clinical medicine WNK Lysine-Deficient Protein Kinase 1 Internal medicine medicine Animals Phosphorylation Renal Insufficiency Chronic Kidney Renal sodium reabsorption urogenital system Chemistry Kinase Tumor Necrosis Factor-alpha medicine.disease WNK1 WNK4 030104 developmental biology medicine.anatomical_structure Endocrinology Nephrology Hypertension |
| Zdroj: | Kidney international. 97(4) |
| ISSN: | 1523-1755 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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