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WNK bodies cluster WNK4 and SPAK/OSR1 to promote NCC activation in hypokalemia.

ABSTRACT: K⁺ deficiency stimulates renal salt reuptake via the Na⁺-Cl^- cotransporter (NCC) of the distal convoluted tubule (DCT), thereby reducing K⁺ losses in downstream nephron segments while increasing NaCl retention and blood pressure. NCC activation is mediated by a kinase cascade involving with no lysine (WNK) kinases upstream of Ste20-related proline-alanine-rich kinase (SPAK) and oxidative stress-responsive kinase-1 (OSR1). In K⁺ deficiency, WNKs and SPAK/OSR1 concentrate in spherical cytoplasmic domains in the DCT termed "WNK bodies," the significance of which is undetermined. By feeding diets of varying salt and K⁺ content to mice and using genetically engineered mouse lines, we aimed to clarify whether WNK bodies contribute to WNK-SPAK/OSR1-NCC signaling. Phosphorylated SPAK/OSR1 was present both at the apical membrane and in WNK bodies within 12 h of dietary K⁺ deprivation, and it was promptly suppressed by K⁺ loading. In WNK4-deficient mice, however, larger WNK bodies formed, containing unphosphorylated WNK1, SPAK, and OSR1. This suggests that WNK4 is the primary active WNK isoform in WNK bodies and catalyzes SPAK/OSR1 phosphorylation therein. We further examined mice carrying a kidney-specific deletion of the basolateral K⁺ channel-forming protein Kir4.1, which is required for the DCT to sense plasma K⁺ concentration. These mice displayed remnant mosaic expression of Kir4.1 in the DCT, and upon K⁺ deprivation, WNK bodies developed only in Kir4.1-expressing cells. We postulate a model of DCT function in which NCC activity is modulated by plasma K⁺ concentration via WNK4-SPAK/OSR1 interactions within WNK bodies.

SUBMITTER: Thomson MN

PROVIDER: S-EPMC6985824 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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WNK bodies cluster WNK4 and SPAK/OSR1 to promote NCC activation in hypokalemia.

Thomson Martin N MN Cuevas Catherina A CA Bewarder Tim M TM Dittmayer Carsten C Miller Lauren N LN Si Jinge J Cornelius Ryan J RJ Su Xiao-Tong XT Yang Chao-Ling CL McCormick James A JA Hadchouel Juliette J Ellison David H DH Bachmann Sebastian S Mutig Kerim K

American journal of physiology. Renal physiology 20191118 1

K+ deficiency stimulates renal salt reuptake via the Na+-Cl- cotransporter (NCC) of the distal convoluted tubule (DCT), thereby reducing K+ losses in downstream nephron segments while increasing NaCl retention and blood pressure. NCC activation is mediated by a kinase cascade involving with no lysine (WNK) kinases upstream of Ste20-related proline-alanine-rich kinase (SPAK) and oxidative stress-responsive kinase-1 (OSR1). In K+ deficiency, W ...[more]

PMID: 31736353

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Project description:Metabolic syndrome patients have insulin resistance, which causes hyperinsulinemia, which in turn causes aberrant increased renal sodium reabsorption. The precise mechanisms underlying this greater salt sensitivity of hyperinsulinemic patients remain unclear. Abnormal activation of the recently identified with-no-lysine kinase (WNK)-oxidative stress-responsive kinase 1 (OSR1)/STE20/SPS1-related proline/alanine-rich kinase (SPAK)-NaCl cotransporter (NCC) phosphorylation cascade results in the salt-sensitive hypertension of pseudohypoaldosteronism type II. Here, we report a study of renal WNK-OSR1/SPAK-NCC cascade activation in the db/db mouse model of hyperinsulinemic metabolic syndrome. Thiazide sensitivity was increased, suggesting greater activity of NCC in db/db mice. In fact, increased phosphorylation of OSR1/SPAK and NCC was observed. In both SpakT243A/+ and Osr1T185A/+ knock-in db/db mice, which carry mutations that disrupt the signal from WNK kinases, increased phosphorylation of NCC and elevated blood pressure were completely corrected, indicating that phosphorylation of SPAK and OSR1 by WNK kinases is required for the increased activation and phosphorylation of NCC in this model. Renal phosphorylated Akt was increased in db/db mice, suggesting that increased NCC phosphorylation is regulated by the phosphatidylinositol 3-kinase/Akt signaling cascade in the kidney in response to hyperinsulinemia. A phosphatidylinositol 3-kinase inhibitor (NVP-BEZ235) corrected the increased OSR1/SPAK-NCC phosphorylation. Another more specific phosphatidylinositol 3-kinase inhibitor (GDC-0941) and an Akt inhibitor (MK-2206) also inhibited increased NCC phosphorylation. These results indicate that the phosphatidylinositol 3-kinase/Akt signaling pathway activates the WNK-OSR1/SPAK-NCC phosphorylation cascade in db/db mice. This mechanism may play a role in the pathogenesis of salt-sensitive hypertension in human hyperinsulinemic conditions, such as the metabolic syndrome.

Dataset Information

WNK bodies cluster WNK4 and SPAK/OSR1 to promote NCC activation in hypokalemia.

Publications

WNK bodies cluster WNK4 and SPAK/OSR1 to promote NCC activation in hypokalemia.

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