Journal article
WNK1-OSR1/SPAK KINASE CASCADE IS IMPORTANT FOR ANGIOGENESIS
Transactions of the American Clinical and Climatological Association, Vol.131, pp.140-146
2020
PMCID: PMC7358493
PMID: 32675854
Abstract
WNK [with-no-lysine (K)] kinases are a family of four members of serine and threonine kinases that regulate renal Na
and K
transport. Mutations of WNK1 and WNK4 cause a hereditary hypertensive and hyperkalemic disease known as pseudohypoaldosteronism type II (PHA2). Unlike other WNK isoforms, WNK1 is ubiquitously expressed and regulates many other cellular processes outside the kidney. Oxidative stress response kinase (OSR1) and related STE 20/SPS1-related proline alanine-rich kinase (SPAK) are downstream kinases of WNK kinases. To examine the role of WNK kinase cascade
, we generated global
-deleted mice and found that
-ablated mice die
from embryonic angiogenesis and cardiac developmental defects. Endothelial-specific
deletion reveals that angiogenesis defect is due to WNK1 requirement in endothelium. We further showed that global and endothelial-deletion of
phenocopies
deletion. Furthermore, expression of a catalytic constitutively active
transgene rescues angiogenesis defects and embryonic lethality of
-ablated mice. In zebrafish,
knockdown causes similar angiogenesis defects to
(
) knockdown and that expression of WNK1 partially rescues
angiogenesis defects. The results indicate that WNK1 is downstream of VEGF signaling cascade. T-lymphocytes isolated from
-null mice exhibit migration defects. Inhibition of WNK1-OSR1 downstream target Na-K-2Cl cotransporter NKCC1 mimics migration defect of WNK1-deficient T-lymphocytes. Thus, WNK1-OSR1/SPAK cascade is important for angiogenesis. Regulation of ion homeostasis and cell volume may underlie the mechanism for WNK1 regulation of endothelial cell migration and angiogenesis.
Details
- Title: Subtitle
- WNK1-OSR1/SPAK KINASE CASCADE IS IMPORTANT FOR ANGIOGENESIS
- Creators
- Chou-Long Huang - IOWA CITY, IOWAXie Jian - IOWA CITY, IOWAChiou-Hwa Yuh - IOWA CITY, IOWA
- Resource Type
- Journal article
- Publication Details
- Transactions of the American Clinical and Climatological Association, Vol.131, pp.140-146
- PMID
- 32675854
- PMCID
- PMC7358493
- ISSN
- 0065-7778
- Grant note
- R01 DK111542 / NIDDK NIH HHS
- Language
- English
- Date published
- 2020
- Academic Unit
- Nephrology; Internal Medicine
- Record Identifier
- 9984362343602771
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