WNK4-mediated regulation of renal ion transport proteins

Abstract

Peng J-B, Warnock DG. WNK4-mediated regulation of renal ion transport proteins. Am J Physiol Renal Physiol 293: F961-F973, 2007. First published July 18, 2007; doi:10.1152/ajprenal.00192.2007], a serine-threonine kinase that is expressed in the distal nephron of the kidney, are linked to familial hyperkalemic hypertension (FHH). The imbalanced electrolyte homeostasis in FHH has led to studies toward an understanding of WNK4-mediated regulation of ion transport proteins in the kidney. A growing number of ion transport proteins for Na, and Cl Ϫ , including ion channels and transporters in the transcellular pathway and claudins in the paracellular pathway, are shown to be regulated by WNK4 from studies using models ranging from Xenopus laevis oocytes to transgenic and knockin mice. WNK4 regulates these transport proteins in different directions and by different cellular mechanisms. The common theme of WNK4-mediated regulation is to alter the abundance of ion transport proteins at the plasma membrane, with the exception of claudins, which are phosphorylated in the presence of WNK4. The regulation of WNK4 can be blocked by the full-length WNK1, whose action is in turn antagonized by a kidney-specific WNK1 variant lacking the kinase domain. In addition, WNK4 also activates stress-related serine-threonine kinases to regulate members of the SLC12 family members of cation-chloride cotransporters. In many cases, the FHH-causing mutants of WNK4 exhibit differences from wild-type WNK4 in regulating ion transport proteins. These regulations well explain the clinical features of FHH and provide insights into the multilayered regulation of ion transport processes in the distal nephron. WNK1; kidney; hypertension; ion channel; transporter THE DISTAL PORTION OF THE nephron, including the distal convoluted tubule (DCT), the connecting tubule (CNT), and the cortical collecting duct (CCT), is important for Na ϩ , K ϩ , and Ca 2ϩ homeostasis (65,80). An array of ion transport proteins located in this portion of the nephron plays important roles in maintaining an electrolyte balance and, in turn, a normal blood pressure. The roles of these ion transport proteins in maintaining a normal blood pressure have been demonstrated in genetic disorders (59,103). For examples, gain-of-function in the amiloride-sensitive epithelial Na ϩ channel (ENaC) causes hypertension in Liddle's syndrome (32, 90); loss-of-function in the thiazide-sensitive Na ϩ -Cl Ϫ cotransporter (NCC; SLC12A3; also known as TSC or NCCT) results in hypotension in Gitelman syndrome (91).The linkage of familial hyperkalemic hypertension (FHH; also known as pseudohypoaldosteronism type II, PHAII, or Gordon's syndrome) (30), an autosomal dominant form of hypertension, to two members of the WNK [With No K (lysine)] family of protein serine-threonine kinases has powered efforts to understand the roles of WNK kinases in regulating ion transporters in the distal tubule (104). The WNK family consists of four members; they all lack an invariant lysine residue in the catalytic site ...

Physiology of Cell Volume Regulation in Vertebrates

“…The WNKs are a family of Ser/Thr protein kinases comprising four mammalian isoforms, WNK1-4 (424,806,1033). They derive their name from a unique substitution in the catalytic core, a cysteine replacing a lysine which is invariant in essentially all other protein kinases (1033).…”

“…WNK1 and WNK4 became the subject of intense research interest when they were found to be mutated in pseudohypoaldosteronism type II (PHA II) or Gordon's syndrome, a rare form of congenital hypertension with hyperkalaemia and metabolic acidosis (1096; see Refs. 424,806). Wildtype WNK4 inhibits NCC in the distal nephron by reducing the number of transport proteins at the plasma membrane, whereas wild-type WNK1 appears to indirectly regulate NCC by inhibiting the effect of WNK4 on the transporter (1096; see Refs.…”

“…Wildtype WNK4 inhibits NCC in the distal nephron by reducing the number of transport proteins at the plasma membrane, whereas wild-type WNK1 appears to indirectly regulate NCC by inhibiting the effect of WNK4 on the transporter (1096; see Refs. 424,806). The WNK mutations associated with PHAII lead to increased WNK1 expression and decreased WNK4 expression, respectively, and the resulting excessive NCC activity is a major factor in the pathophysiology of PHAII (see Refs.…”

“…The WNK mutations associated with PHAII lead to increased WNK1 expression and decreased WNK4 expression, respectively, and the resulting excessive NCC activity is a major factor in the pathophysiology of PHAII (see Refs. 424,806).…”

“…Thus WNK1 activates SGK1, SGK1 phosphorylates WNK4 leading to abrogation of WNK4 effects on ENaC and ROMK, and the three kinases physically interact (847; see Ref. 806). The possible relevance of this to cell volume regulation is, however, not straightforward, as SGK1 transcription is increased, yet the activity of the expressed protein decreased, by hypertonic stress (1059; see Ref.…”