Anti-WNK1 polyclonal antibody

Purpose of review This review summarizes recent advances in the understanding of the mechanism of regulation of renal ion transport by WNK kinases. Recent findings There are four mammalian WNK [with-no-lysine (K)] kinases: WNK1--WNK4. Mutations of WNK1 and INNK4 in humans cause hypertension and hyperkalemia at least partly by altering renal sodium and potassium transport. WNK1 and WNK4 stimulate endocytosis of ROMK1 by recruiting an endocytic scaffold protein, intersectin. The recruitment is independent of the kinase activity and occurs between the PXXP motif of WNKs and the SH3 domain of intersectin. Regulation of cation-chloride-cou pled cotransporters, Na+-K+-2Cl(-) cotransporter (NKCC) 1 and NKCC2 [and the Na-Cl cotransporter (NCC), undersome conditions] by WNKs requires kinase activity. WNK1 and WNK4 bind with and phosphorylate two Ste20-related protein kinases, OSR1 and SPAK, which in turn bind with and phosphorylate NKCCs and NCC to increase their activity. Binding of OSR1/SPAK to upstream activators (WNKs) and downstream substrates (NKCCs and NCC) are both mediated by a docking site ill the C-terminus of OSR1/SPAK and RFX[V/1] motifs present in WNKs or in NKCCs and NCC. Summary WNKs regulate ion transport via both catalytic and noncatalytic mechanisms. We discuss hypotheses that WNKs, contrasting with aldosterone, play important roles in dissociating sodium reabsorption from potassium secretion.

The distal nephron, which is the site of the micro-regulation of water absorption and ion handling in the kidneys, is under the control of aldosterone. Impairment of the mineralocorticoid signal transduction pathway results in resistance to the action of aldosterone and of mineralocorticoids in general. Herein, we review two syndromes in which ion handling in the distal nephron is impaired: pseudohypoaldosteronism (PHA) and familial hyperkalemic hypertension (FHH). PHA is a rare inherited syndrome characterized by mineralocorticoid resistance, which leads to salt loss, hypotension, hyperkalemia and metabolic acidosis. There are two types of this syndrome: a renal (autosomal dominant) type due to mutations of the mineralocorticoid receptor (MR), and a systemic (autosomal recessive) type due to mutations of the epithelial sodium channel (ENaC). There is also a transient form of PHA, which may be due to urinary tract infections, obstructive uropathy or several medications. FHH is a rare autosomal dominant syndrome, characterized by salt retention, hypertension, hyperkalemia and metabolic acidosis. In FHH, mutations of WNK (with-no-lysine kinase) 4 and 1 alter the activity of several ion transportation systems in the distal nephron. The study of the pathophysiology of PHA and FHH greatly elucidated our understanding of the renin-angiotensin-aldosterone system function and ion handling in the distal nephron. The physiological role of the distal nephron and the pathophysiology of diseases in which the renal tubule is implicated may hence be better understood and, based on this understanding, new drugs can be developed.