A γGT-AT1A receptor transgene protects renal cortical structure in AT1 receptor-deficient mice

Thu H. Le, Michael I. Oliverio, Hyung Suk Kim, Harmony Salzler, Rajesh C. Dash, David N. Howell, Oliver Smithies, Sarah Bronson, Thomas M. Coffman

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13 Scopus citations

Abstract

To understand the physiological role of angiotensin type 1 (AT1) receptors in the proximal tubule of the kidney, we generated a transgenic mouse line in which the major murine AT1 receptor isoform, AT 1A, was expressed under the control of the P1 portion of the γ-glutamyl transpeptidase (γGT) promoter. In transgenic mice, this promoter has been shown to confer cell-specific expression in epithelial cells of the renal proximal tubule. To avoid random integration of multiple copies of the transgene, we used gene targeting to produce mice with a single-copy transgene insertion at the hypoxanthine phosphoribosyl transferase (Hprt) locus on the X chromosome. The physiological effects of the γGT-AT1A transgene were examined on a wild-type background and in mice with targeted disruption of one or both of the murine AT1 receptor genes (Agtr1a and Agtr1b). On all three backgrounds, γGT-AT1A transgenic mice were healthy and viable. On the wild-type background, the presence of the transgene did not affect development, blood pressure, or kidney structure. Despite relatively low levels of expression in the proximal tubule, the transgene blunted the increase in renin expression typically seen in AT 1-deficient mice and partially rescued the kidney phenotype associated with Agtr1a-/-Agtr1b-/- mice, significantly reducing cortical cyst formation by more than threefold. However, these low levels of cell-specific expression of AT1 receptors in the renal proximal tubule did not increase the low blood pressures or abolish sodium sensitivity, which are characteristic of AT1 receptor-deficient mice. Although our studies do not clearly identify a role for AT1 receptors in the proximal tubules of the kidney in blood pressure homeostasis, they support a major role for these receptors in modulating renin expression and in maintaining structural integrity of the renal cortex.

Original languageEnglish (US)
Pages (from-to)290-298
Number of pages9
JournalPhysiological genomics
Volume18
DOIs
StatePublished - Oct 2004

All Science Journal Classification (ASJC) codes

  • Physiology
  • Genetics

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    Le, T. H., Oliverio, M. I., Kim, H. S., Salzler, H., Dash, R. C., Howell, D. N., Smithies, O., Bronson, S., & Coffman, T. M. (2004). A γGT-AT1A receptor transgene protects renal cortical structure in AT1 receptor-deficient mice. Physiological genomics, 18, 290-298. https://doi.org/10.1152/physiolgenomics.00120.2003