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Renal‐tubular NEDD4‐2 action is fundamental for renal adaptation during potassium deficiency
Author(s) -
Staub Olivier,
Basquin Denis,
Roy Ankita,
Stifanelli Matteo,
Rajaram Renuga Devi,
Maillard Marc,
Subramanya Arohan R,
AlQusairi Lama
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1223.14
Subject(s) - epithelial sodium channel , nedd4 , chemistry , homeostasis , medicine , endocrinology , kidney , ubiquitin ligase , aldosterone , reabsorption , microbiology and biotechnology , ubiquitin , biochemistry , sodium , biology , organic chemistry , gene
The adaptation to K + deficiency requires high coordination between organs involved in K + homeostasis including kidney, muscle and liver. However, how the kidney performs functional and molecular changes to ensure K + retention is not well understood. Here, we show that the ubiquitin‐protein ligase NEDD4‐2, known as a negative regulator of ENaC, NCC and more recently WNK1, is essential for the adaptation of the kidney to potassium deficiency. Our analyses revealed that the induciblerenal‐tubular NEDD4‐2 (NEDD4‐2 Pax8/LC1 ) mice have normal K + homeostasis when challenged by high K + (HKD) or low K + (LKD)diet for one week. Upon longer exposure to LKD (2 weeks), mutant mice exhibited hypokalemia together with increased urinary K + loss. Under the sehypokalemic conditions, increase of the large, Ca 2+ ‐activated K + channel BK and decrease of ROMK protein levels and membrane localization are observed in NEDD4‐2 Pax8/LC1 mice. SPAK‐mediated NCC phosphorylation was enhanced in the knock‐out animals with no change in total NCC. Moreover, the mutant mice showed increased WNK1 signaling in the CNT and the CD, which may explain these deregulations. In addition, ENaC expression and activity were both enhanced in the mutant mice. Interestingly, IP injection of Benzamil, anENaC inhibitor, restored K + loss in NEDD4‐2 Pax8/LC1 mice. Altogether, our data strongly suggest that NEDD4‐2plays an essential role in K + retention via coordination of K + channels including BK and ROMK on the one hand and of Na + transporters including ENaC and NCC on the other hand. Support or Funding Information Swiss National Science Foundation grant 310030_159735 (to OS), Swiss Kidney.ch NCCR (to OS), National Institutes of Health grant DK098145 (to ARS). LAQ was supported by a fellowship of the Marie Curie Co‐funding IKPP (International Fellowship Program on Integrative Kidney Physiology and Pathophysiology).