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Genetic evidence that lethality in angiotensinogen-deficient mice is due to loss of systemic but not renal angiotensinogen. J Biol Chem 2001 Mar 09;276(10):7431-6

Date

11/30/2000

Pubmed ID

11096065

DOI

10.1074/jbc.M003892200

Scopus ID

2-s2.0-0035831441   17 Citations

Abstract

Angiotensinogen (AGT)-deficient mice die shortly after birth presumably due to renal dysfunction caused by the presence of severe vascular and tubular lesions in the kidney. Because AGT is expressed in renal proximal tubule cells, we hypothesized that its loss may be the primary mediator of the lethal phenotype. We generated two models to test this hypothesis by breeding transgenic mice expressing human renin with mice expressing human AGT (hAGT) either systemically or kidney-specifically. We then bred double transgenic mice with AGT+/- mice, intercrossed the compound heterozygotes, and examined the offspring. We previously reported that the presence of the human renin and systemically expressed hAGT transgene complemented the lethality observed in AGT-/- mice. On the contrary, we show herein that the presence of the human renin and kidney-specific hAGT transgene cannot rescue lethality in AGT-/- mice. An analysis of newborns indicated that AGT-/- mice were born in normal numbers, and collection of dead 10-day old pups revealed an enrichment in AGT-/-. Importantly, we demonstrated that angiotensinogen protein and functional angiotensin II was generated in the kidney, and the kidney-specific transgene was temporally expressed during renal development similar to the endogenous AGT gene. These data strongly support the notion that the loss of systemic AGT, but not intrarenal AGT, is responsible for death in the AGT-/- mouse model. Taken together with our previous studies, we conclude that the intrarenal renin-angiotensin system located in the proximal tubule plays an important role in blood pressure regulation and may cause hypertension if overexpressed, but may not be required for continued development of the kidney after birth.

Author List

Ding Y, Stec DE, Sigmund CD

Author

Curt Sigmund PhD Chair, Professor in the Physiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Alleles
Angiotensin II
Angiotensinogen
Animals
Animals, Newborn
Blotting, Southern
Crosses, Genetic
Female
Genetic Complementation Test
Genotype
Humans
Kidney
Male
Mice
Mice, Transgenic
Microscopy, Confocal
Phenotype
Renin
Sex Factors
Time Factors