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Tomilin VN, Pyrshev K, Stavniichuk A, et al. Epac1-/- and Epac2-/- mice exhibit deficient epithelial Na+ channel regulation and impaired urinary Na+ conservation. JCI Insight. 2021;doi: 10.1172/jci.insight.145653.
Tomilin, V. N., Pyrshev, K., Stavniichuk, A., Hassanzadeh Khayyat, N., Ren, G., Zaika, O., Khedr, S., Staruschenko, A., Mei, F. C., Cheng, X., & Pochynyuk, O. (2021). Epac1-/- and Epac2-/- mice exhibit deficient epithelial Na+ channel regulation and impaired urinary Na+ conservation. JCI insight, . https://doi.org/10.1172/jci.insight.145653
Tomilin, Victor N, et al. "Epac1-/- and Epac2-/- mice exhibit deficient epithelial Na+ channel regulation and impaired urinary Na+ conservation." JCI insight vol. (2021). doi: https://doi.org/10.1172/jci.insight.145653
Tomilin VN, Pyrshev K, Stavniichuk A, Hassanzadeh Khayyat N, Ren G, Zaika O, Khedr S, Staruschenko A, Mei FC, Cheng X, Pochynyuk O. Epac1-/- and Epac2-/- mice exhibit deficient epithelial Na+ channel regulation and impaired urinary Na+ conservation. JCI Insight. 2021 Dec 16; doi: 10.1172/jci.insight.145653. Epub 2021 Dec 16. PMID: 34914636.
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JCI Insight. 2021 Dec 16; doi: 10.1172/jci.insight.145653. Epub 2021 Dec 16.

Epac1-/- and Epac2-/- mice exhibit deficient epithelial Na+ channel regulation and impaired urinary Na+ conservation.

JCI insight

Victor N Tomilin, Kyrylo Pyrshev, Anna Stavniichuk, Naghmeh Hassanzadeh Khayyat, Guohui Ren, Oleg Zaika, Sherif Khedr, Alexander Staruschenko, Fang C Mei, Xiaodong Cheng, Oleh Pochynyuk

Affiliations

  1. Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, United States of America.
  2. Department of Physiology, Medical College of Wisconsin, Milwuakee, United States of America.
  3. The University of Texas Health Science Center at Houston, Houston, United States of America.

PMID: 34914636 DOI: 10.1172/jci.insight.145653

Abstract

Exchange proteins directly activated by cAMP (Epacs) are abundantly expressed in the renal tubules. We used genetic and pharmacological tools in combination with balance, electrophysiological and biochemical approaches to examine the role of Epac1 and Epac2 in renal sodium handling. We demonstrate that Epac1-/- and Epac2-/- mice exhibit a delayed anti-natriuresis to dietary sodium restriction despite augmented aldosterone levels. This was associated with a significantly lower response to the epithelial Na+ channel (ENaC) blocker amiloride, reduced ENaC activity in split-opened collecting ducts, and defective posttranslational processing of α and γENaC subunits in the knockout mice fed with Na+ deficient diet. Concomitant deletion of both isoforms led to a marginally greater natriuresis but further increased aldosterone levels. Epac2 blocker, ESI-05 and Epac1&2 blocker, ESI-09 decreased ENaC activity in EpacWT mice kept on Na+ deficient diet but not on the regular diet. ESI-09 injections led to natriuresis in EpacWT mice on Na+ deficient diet, which was caused by ENaC inhibition. In summary, our results demonstrate non-redundant actions of Epac1 and Epac2 in stimulation of ENaC activity during variations in dietary salt intake. We speculate that inhibition of Epac signaling could be instrumental in treatment of hypertensive states associated with ENaC over-activation.

Keywords: Epithelial transport of ions and water; Ion channels; Nephrology; Sodium channels

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