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Role of K ir 4.1 ( Kcnj10 ) in the Regulation of Salt‐Induced Hypertension
Author(s) -
Manis Anna D.,
Levchenko Vladislav,
Alvarez Santiago,
Geurts Aron M.,
Dwinell Melinda R.,
Hodges Matthew R.,
Staruschenko Alexander,
Palygin Oleg
Publication year - 2020
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.2020.34.s1.02172
Subject(s) - endocrinology , aldosterone , medicine , kidney , chemistry , blood pressure , frameshift mutation , renin–angiotensin system , homeostasis , angiotensin ii , biology , exon , gene , biochemistry
In the kidney, K ir 4.1 ( Kcnj10 ) and K ir 5.1 ( Kcnj16 ) are highly expressed in the aldosterone sensitive distal nephron (ASDN), a major target for multiple hormones controlling blood pressure. These basolateral inwardly rectifying potassium channel subunits assemble to form both heteromeric K ir 4.1/K ir 5.1 channels and homomeric K ir 4.1 channels. These channels control the transepithelial voltage, fine‐tune renal electrolyte homeostasis and contribute to long‐term blood pressure control, correspondingly. To study the role of K ir 4.1 containing channels in the renal control of blood pressure, renin‐angiotensin‐aldosterone system (RAAS) balance, and salt‐sensitive (SS) hypertension, we created a Kcnj10 knockout (SS Kcnj10−/− ) on the Dahl SS rat background. The SS Kcnj10−/− rat was created using CRISPR/Cas9 mutagenesis, resulting in a single base pair insertion in exon 2 of the Kcnj10 gene and producing a frameshift in K ir 4.1 protein translation after only 26 amino acids. Homozygous SS Kcnj10−/− rats were hypokalemic, had reduced heart, kidney, and body weights, and did not survive more than 3 weeks after birth. Mass spectrometry based quantification of serum RAAS peptides revealed increased Ang I (1631 vs. 560 pM), Ang 1–5 (499 vs. 69 pM), and Ang 1–7 (598 vs. 42 pM) levels in SS Kcnj10−/− rats compared to age‐matched SS Kcnj10+/+ controls. No differences were observed in serum Ang II, Ang III, Ang IV, or aldosterone levels. In addition, ACE activity represented by the Ang II to Ang I ratio was decreased in SS Kcnj10−/− rats (0.58 vs. 1.1). The increases in alternative RAS axis peptides (Ang 1–5 and Ang 1–7) and decrease in ACE activity in SS Kcnj10−/− rats are suggestive of a low blood pressure phenotype, however, their limited survival precluded blood pressure measurement. Heterozygous (SS Kcnj10+/− ) developed normally and showed no changes in serum electrolytes. Although survival rate of both male and female SS Kcnj10+/− rats was dramatically lower compared to SS Kcnj10+/+ rats, they were able to survive much longer than SS Kcnj10−/− rats (21 vs. 83 days on average, respectively) with dietary K + supplementation (HK; 1.41% K + ), allowing for telemetric blood pressure measurement. We found no differences in baseline blood pressure under control conditions (LS+HK; 123±2 vs 125±4, mmHg), but salt‐induced (HS, 4% NaCl) elevations in blood pressure were significantly attenuated in SS Kcnj10+/− rats fed a HS diet (149±6 vs 183±9 mmHg for SS Kcnj10+/− and SS Kcnj10+/+ rats, respectively). Furthermore, after 3 weeks on HS, SS Kcnj10+/− rats showed decreased diuresis (25±5 vs 38±2, ml/day) and improved albuminuria (6.0±4.0 vs 17.2±7.6, Alb/Cre ratio) compared to SS Kcnj10+/+ rats. Our results demonstrate that renal K ir 4.1 containing channels mediate salt‐sensitive increases in blood pressure through regulation of potassium homeostasis, modulation of alternative RAS axis hormones, and control of renal salt handling in the ASDN. Support or Funding Information Supported by the National Institutes of Health grants R35 HL135749, R56 DK121750, R24 HL114474, and F31 DK122647