Downregulation of NCC and NKCC2 cotransporters by kidney-specific WNK1 revealed by gene disruption and transgenic mouse models.
WNK1 (with-no-lysine[K]-1) is a protein kinase of which mutations cause a familial hypertension and hyperkalemia syndrome known as pseudohypoaldosteronism type 2 (PHA2). Kidney-specific (KS) WNK1 is an alternatively spliced form of WNK1 kinase missing most of the kinase domain. KS-WNK1 downregulates the Na(+)-Cl(-) cotransporter NCC by antagonizing the effect of full-length WNK1 when expressed in Xenopus oocytes. The physiological role of KS-WNK1 in the regulation of NCC and potentially other Na(+) transporters in vivo is unknown. Here, we report that mice overexpressing KS-WNK1 in the kidney exhibited renal Na(+) wasting, elevated plasma levels of angiotensin II and aldosterone yet lower blood pressure relative to wild-type littermates. Immunofluorescent staining revealed reduced surface expression of total and phosphorylated NCC and the Na(+)-K(+)-2Cl(-) cotransporter NKCC2 in the distal convoluted tubule and the thick ascending limb of Henle's loop, respectively. Conversely, mice with targeted deletion of exon 4A (the first exon for KS-WNK1) exhibited Na(+) retention, elevated blood pressure on a high-Na(+) diet and increased surface expression of total and phosphorylated NCC and NKCC2 in respective nephron segments. Thus, KS-WNK1 is a negative regulator of NCC and NKCC2 in vivo and plays an important role in the control of Na(+) homeostasis and blood pressure. These results have important implications to the pathogenesis of PHA2 with WNK1 mutations.
Pubmed ID: 21131289 RIS Download
Amino Acid Sequence | Animals | Blood Pressure | Disease Models, Animal | Down-Regulation | Female | Gene Expression Regulation | Gene Silencing | Humans | Kidney | Male | Mice | Mice, Inbred C57BL | Mice, Knockout | Mice, Transgenic | Molecular Sequence Data | Organ Specificity | Protein Structure, Tertiary | Protein-Serine-Threonine Kinases | Pseudohypoaldosteronism | Receptors, Drug | Sodium | Sodium-Potassium-Chloride Symporters | Solute Carrier Family 12, Member 1 | Solute Carrier Family 12, Member 3 | Symporters