A gammaGT-AT1A receptor transgene protects renal cortical structure in AT1 receptor-deficient mice.
To understand the physiological role of angiotensin type 1 (AT(1)) receptors in the proximal tubule of the kidney, we generated a transgenic mouse line in which the major murine AT(1) receptor isoform, AT(1A), was expressed under the control of the P1 portion of the gamma-glutamyl transpeptidase (gammaGT) 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 gammaGT-AT(1A) transgene were examined on a wild-type background and in mice with targeted disruption of one or both of the murine AT(1) receptor genes (Agtr1a and Agtr1b). On all three backgrounds, gammaGT-AT(1A) 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 AT(1) receptors in the renal proximal tubule did not increase the low blood pressures or abolish sodium sensitivity, which are characteristic of AT(1) receptor-deficient mice. Although our studies do not clearly identify a role for AT(1) 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.
Department of Medicine, Duke University and Durham Veterans Affairs Medical Centers, Durham 27705, USA.
Thu H
TH
Le
Michael I
MI
Oliverio
Hyung-Suk
HS
Kim
Harmony
H
Salzler
Rajesh C
RC
Dash
David N
DN
Howell
Oliver
O
Smithies
Sarah
S
Bronson
Thomas M
TM
Coffman
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D018390:Gene Targeting / Q000379:methods; D005819:Genetic Markers / Q000235:genetics; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D007671:Kidney Concentrating Ability / Q000502:physiology; D007672:Kidney Cortex / Q000737:chemistry* / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology; D012083:Renin / Q000096:biosynthesis; D013534:Survival / Q000502:physiology; D019076:Transgenes / Q000502:physiology*; D014960:X Chromosome / Q000235:genetics; D005723:gamma-Glutamyltransferase / Q000235:genetics / Q000502:physiology*
D005819:Genetic Markers; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D011993:Recombinant Fusion Proteins; D005723:gamma-Glutamyltransferase; D007041:Hypoxanthine Phosphoribosyltransferase; D012083:Renin