Overexpression of human WNK1 increases paracellular chloride permeability and phosphorylation of claudin-4 in MDCKII cells
- 20 October 2006
- journal article
- Published by Elsevier BV in Biochemical and Biophysical Research Communications
- Vol. 349 (2), 804-808
- https://doi.org/10.1016/j.bbrc.2006.08.101
Abstract
Pseudohypoaldosteronism type II (PHAII), an autosomal dominant disorder characterized by hypertension, hyperkalemia, and hyperchloremic acidosis, is reportedly due to mutations in WNK1 and WNK4 kinase genes. However, the pathogenesis of the disease remains unknown. Mutations in the WNK1 gene are the deletions in the first intron, which reportedly increases WNK1 mRNA expression. Thus, we generated WNK1 over-expressing stable cell lines using MDCKII cells to model the distal nephron of PHAII patients. Using these cell lines, we investigated whether increased WNK1 expression might affect paracellular chloride permeability and claudin phosphorylation, since we previously observed an increase in both with a disease-causing mutant WNK4. WNK1 expression in MDCKII cells increased chloride permeability two to threefold. Co-expression of wild-type WNK4 did not further increase WNK1-enhanced chloride permeability. WNK1 expression also induced phosphorylation of endogenous claudin-4 in MDCKII cells, as well as over-expressed claudin-4. Combined, these results suggest that increased WNK1 expression has the same effect on chloride permeability and claudin phosphorylation as the mutant WNK4. Thus, increased chloride shunt may be involved in the pathogenesis of PHAII caused by WNK1 mutations.Keywords
This publication has 24 references indexed in Scilit:
- Functional interactions of the SPAK/OSR1 kinases with their upstream activator WNK1 and downstream substrate NKCC1Biochemical Journal, 2006
- Dominant-negative regulation of WNK1 by its kidney-specific kinase-defective isoformAmerican Journal of Physiology-Renal Physiology, 2006
- Aldosterone and tight junctions: modulation of claudin-4 phosphorylation in renal collecting duct cellsAmerican Journal of Physiology-Cell Physiology, 2005
- The WNK1 and WNK4 protein kinases that are mutated in Gordon's hypertension syndrome phosphorylate and activate SPAK and OSR1 protein kinasesBiochemical Journal, 2005
- WNK kinases, a novel protein kinase subfamily in multi-cellular organismsOncogene, 2001
- Human Hypertension Caused by Mutations in WNK KinasesScience, 2001
- Conversion of Zonulae Occludentes from Tight to Leaky Strand Type by Introducing Claudin-2 into Madin-Darby Canine Kidney I CellsThe Journal of cell biology, 2001
- WNK1, a Novel Mammalian Serine/Threonine Protein Kinase Lacking the Catalytic Lysine in Subdomain IIJournal of Biological Chemistry, 2000
- Syndrome of hypertension and hyperkalemia with normal glomerular filtration rate.Hypertension, 1986
- Mineralocorticoid-resistant renal hyperkalemia without salt wasting (type II pseudohypoaldosteronism): Role of increased renal chloride reabsorptionKidney International, 1981