Heterozygous disruption of renal outer medullary potassium channel in rats is associated with reduced blood pressure

Xiaoyan Zhou, Zuo Zhang, Myung Kyun Shin, Sarah Beth Horwitz, John M. Levorse, Lei Zhu, Wanda Sharif-Rodriguez, Denis Y. Streltsov, Maya Dajee, Melba Hernandez, Yi Pan, Olga Urosevic-Price, Li Wang, Gail Forrest, Daphne Szeto, Yonghua Zhu, Yan Cui, Bindhu Michael, Leslie Ann Balogh, Paul A. WellingJames B. Wade, Sophie Roy, Kathleen A. Sullivan

Research output: Contribution to journalArticle

Abstract

The renal outer medullary potassium channel (ROMK, KCNJ1) mediates potassium recycling and facilitates sodium reabsorption through the Na +/K+/2Cl- cotransporter in the loop of Henle and potassium secretion at the cortical collecting duct. Human genetic studies indicate that ROMK homozygous loss-of-function mutations cause type II Bartter syndrome, featuring polyuria, renal salt wasting, and hypotension; humans heterozygous for ROMK mutations identified in the Framingham Heart Study have reduced blood pressure. ROMK null mice recapitulate many of the features of type II Bartter syndrome. We have generated an ROMK knockout rat model in Dahl salt-sensitive background by using zinc finger nuclease technology and investigated the effects of knocking out ROMK on systemic and renal hemodynamics and kidney histology in the Dahl salt-sensitive rats. The ROMK-/- pups recapitulated features identified in the ROMK null mice. The ROMK +/- rats, when challenged with a 4% salt diet, exhibited a reduced blood pressure compared with their ROMK+/+ littermates. More importantly, when challenged with an 8% salt diet, the Dahl salt-sensitive rats with 50% less ROMK expression showed increased protection from salt-induced blood pressure elevation and signs of protection from renal injury. Our findings in ROMK knockout Dahl salt-sensitive rats, together with the previous reports in humans and mice, underscore a critical role of ROMK in blood pressure regulation.

Original languageEnglish (US)
Pages (from-to)288-294
Number of pages7
JournalHypertension
Volume62
Issue number2
DOIs
StatePublished - Aug 1 2013
Externally publishedYes

Keywords

  • Dahl salt-resistant rats
  • Gene knockout
  • Hypertension
  • Kcnj1 protein, rat
  • ROMK protein, rat
  • Renal insufficiency, acute

ASJC Scopus subject areas

  • Internal Medicine

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  • Cite this

    Zhou, X., Zhang, Z., Shin, M. K., Horwitz, S. B., Levorse, J. M., Zhu, L., Sharif-Rodriguez, W., Streltsov, D. Y., Dajee, M., Hernandez, M., Pan, Y., Urosevic-Price, O., Wang, L., Forrest, G., Szeto, D., Zhu, Y., Cui, Y., Michael, B., Balogh, L. A., ... Sullivan, K. A. (2013). Heterozygous disruption of renal outer medullary potassium channel in rats is associated with reduced blood pressure. Hypertension, 62(2), 288-294. https://doi.org/10.1161/HYPERTENSIONAHA.111.01051