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Home  > Press Release  > Renal TNFα activates WNK phosphorylation cascade and contributes to salt-sensitive hypertension in chronic kidney disease

Renal TNFα activates WNK phosphorylation cascade and contributes to salt-sensitive hypertension in chronic kidney disease

Abstract

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.

Journal Article

JOURNAL:
Kidney International

TITLE:
Estradiol/GPER affects the integrity of mammary duct-like structures in vitroRenal TNFα activates WNK phosphorylation cascade and contributes to salt-sensitive hypertension in chronic kidney disease

DOI:
https://doi.org/10.1016/j.kint.2019.11.021

Correspondence to

Sohara Eisei, Ph.D., Associate Professor
Nephrology,
Graduated School of Medical and Dental Sciences,
Tokyo Medical and Dental University(TMDU)
E-mail:esohara.kid(at)tmd.ac.jp



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