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Renal phenotype of inwardly rectifying potassium channel Kcnj16 (Kir 5.1) knockout in the Dahl salt‐sensitive rats (893.16)
Author(s) -
Palygin Oleg,
Levchenko Vladislav,
Lowing Andrea,
Ilatovskaya Daria,
Pavlov Tengis,
Geurts Aron,
Jacob Howard,
Staruschenko Alexander
Publication year - 2014
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.28.1_supplement.893.16
Subject(s) - medicine , endocrinology , context (archaeology) , homeostasis , knockout mouse , potassium channel , chemistry , kidney , wild type , potassium , gene knockout , biology , biochemistry , gene , receptor , mutant , organic chemistry , paleontology
The inward‐rectifying channels play an important role in the control of resting membrane potential and tubular homeostasis in the kidney. To illuminate the importance of Kcnj16 (Kir 5.1) in the context of a disease state in vivo, we generated a Kcnj16 knockout rat model in Dahl salt‐sensitive (SS) background by using zinc finger nuclease (ZFN) technology. ZFN against Kcnj16 caused a 18‐bp in‐frame deletion that occurred in the second protein transmembrane domain. IHC analysis demonstrated highly specific expression of Kcnj16 on the basolateral membranes of cortical collecting ducts and distal convoluted tubules in the control kidneys of SS and Sprague Dawley rats, which was completely abolished in Kcnj16‐/‐ rats; thus, successful knock out of this protein and consequent degradation of the channel in renal tubules were shown. The mean arterial pressure was significantly lower in Kcnj16‐/‐ compared to wild type SS rats (91.3±1.8 to 104.7±5.5 mmHg) when animals were fed a low salt (0.4%) diet. BUN, potassium and magnesium plasma concentrations were significantly modulated in knock out rats. Urea electrolyte balance was also disturbed compared to wild type animals. Importantly, change of the diet to high salt (4%) chow resulted in mortality of KO rats within 1‐2 days. These data demonstrate critical role of Kcnj16 channels in renal salt handling and in the development of salt‐sensitive hypertension. Grant Funding Source : Supported by NIH HL108880 and ADA 1‐10‐BS‐168 to A.S., NHLBI 5RC2HL101681 to H.J.J