title: Genetic evidence that lethality in angiotensinogen-deficient mice is due to loss of systemic but not renal angiotensinogen.
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.
authors.affiliation: Genetics Interdisciplinary Graduate Program, The University of Iowa College of Medicine, Iowa City, Iowa 52242, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Ding
authors.forename: D E
authors.initials: DE
authors.lastname: Stec
authors.forename: C D
authors.initials: CD
authors.lastname: Sigmund
mesh_terms: D000483:Alleles; D000804:Angiotensin II / Q000096:biosynthesis; D000808:Angiotensinogen / Q000235:genetics* / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D015139:Blotting, Southern; D003433:Crosses, Genetic; D005260:Female; D005816:Genetic Complementation Test; D005838:Genotype; D006801:Humans; D007668:Kidney / Q000196:embryology / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D010641:Phenotype; D012083:Renin / Q000096:biosynthesis; D012737:Sex Factors; D013997:Time Factors
chemical_list: D000808:Angiotensinogen; D000804:Angiotensin II; D012083:Renin