Abstract
The physiological role of the shorter isoform of with no lysine kinase (WNK)1 that is exclusively expressed in the kidney (KS-WNK1), with particular abundance in the distal convoluted tubule, remains elusive. KS-WNK1, despite lacking the kinase domain, is nevertheless capable of stimulating the NaCl cotransporter, apparently through activation of WNK4. It has recently been shown that a less severe form of familial hyperkalemic hypertension featuring only hyperkalemia is caused by missense mutations in the WNK1 acidic domain that preferentially affect cullin 3 (CUL3)-Kelch-like protein 3 (KLHL3) E3-induced degradation of KS-WNK1 rather than that of full-length WNK1. Here, we show that full-length WNK1 is indeed less impacted by the CUL3-KLHL3 E3 ligase complex compared with KS-WNK1. We demonstrated that the unique 30-amino acid NH2-terminal fragment of KS-WNK1 is essential for its activating effect on the NaCl cotransporter and recognition by KLHL3. We identified specific amino acid residues in this region critical for the functional effect of KS-WNK1 and KLHL3 sensitivity. To further explore this, we generated KLHL3-R528H knockin mice that mimic human mutations causing familial hyperkalemic hypertension. These mice revealed that the KLHL3 mutation specifically increased expression of KS-WNK1 in the kidney. We also observed that in wild-type mice, the expression of KS-WNK1 was only detectable after exposure to a low-K+ diet. These findings provide new insights into the regulation and function of KS-WNK1 by the CUL3-KLHL3 complex in the distal convoluted tubule and indicate that this pathway is regulated by dietary K+ levels.NEW & NOTEWORTHY In this work, we demonstrated that the kidney-specific isoform of with no lysine kinase 1 (KS-WNK1) in the kidney is modulated by dietary K+ and activity of the ubiquitin ligase protein Kelch-like protein 3. We analyzed the role of different amino acid residues of KS-WNK1 in its activity against the NaCl cotransporter and sensitivity to Kelch-like protein 3.
Highlights
Familial hyperkalemic hypertension (FHHt) encompasses a spectrum of diseases that are mainly the consequence of overactivity of the renal thiazide-sensitive NaCl cotransporter (NCC) of the distal convoluted tubule (DCT) [1]
As previously reported for a Kelch-like protein 3 (KLHL3) þ /R528H strain generated by Susa and collaborators [22], higher WNK4 and NCC expression levels as well as higher NCC (Thr60) and SPS1related proline-alanine-rich protein kinase (SPAK) (Ser373) phosphorylation levels were observed in KLHL3 þ /R528H mice compared with wild-type mice
We show that KS-WNK1 is more sensitive to cullin 3 (CUL3)-KLHL3 E3-mediated degradation than L
Summary
Familial hyperkalemic hypertension (FHHt) encompasses a spectrum of diseases that are mainly the consequence of overactivity of the renal thiazide-sensitive NaCl cotransporter (NCC) of the distal convoluted tubule (DCT) [1]. The more severe disease presentation is due to exon 9 deletion of CUL3, followed by dominant or recessive mutations in KLHL3 [2, 3]. Less severe is FHHt due to missense mutations in the acidic motif of WNK4, which constitutes the recognition site for KLHL3 [4, 5] and abrogate only WNK4 ubiquitylation [6]. The mildest form of FHHt is due to intronic deletions in the WNK1 gene that apparently result in ectopic expression of the fulllength catalytic isoform of this kinase (known as L-WNK1) in the DCT [7]. Humans and mice with heterozygous mutations in the acidic domain of WNK1 display an inherited phenotype with hyperkalemia, hyperchloremia, and metabolic acidosis, but without arterial hypertension, that is accompanied by low renin expression levels, suggesting a mild volume expansion that is, not enough to produce hypertension
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