Reduced hypertension-induced end-organ damage in mice lacking cardiac and renal angiotensinogen synthesis.
Hypertension-induced damage of kidney and heart is of major clinical relevance, but its pathophysiology is only partially understood. As there is considerable evidence for involvement of angiotensin II, we generated a new mouse model by breeding angiotensinogen (AOGEN) deficient mice with transgenic animals expressing the rat AOGEN gene only in brain and liver. This genetic manipulation overcame the hypotension of AOGEN-deficient mice and even caused hypertension indistinguishable in its extent from the parent transgenic mice with an intact endogenous AOGEN gene. In contrast to normal mice, however, crossbred animals lacked detectable expression of AOGEN in kidney and heart. As a consequence they showed markedly reduced cardiac hypertrophy and fibrosis. Furthermore, hypertension-induced alterations in kidney histology and function were less pronounced in crossbred mice than in equally hypertensive animals expressing AOGEN locally. The dysmorphogenesis observed in kidneys from AOGEN-deficient mice was absent in mice expressing this gene only in liver and brain. Our results support an important role of local AOGEN expression in hypertension-induced end-organ damage but not in the development of the kidney.
Kang
Ningling
N
Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, Berlin-Buch, Germany.
Walther
Thomas
T
Tian
Xiao-Li
XL
Bohlender
Jürgen
J
Fukamizu
Akiyoshi
A
Ganten
Detlev
D
Bader
Michael
M
D000808:Angiotensinogen / Q000172:deficiency / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000502:physiology; D006332:Cardiomegaly / Q000235:genetics; D004195:Disease Models, Animal; D005355:Fibrosis; D006331:Heart Diseases / Q000209:etiology / Q000503:physiopathology; D006973:Hypertension / Q000150:complications* / Q000235:genetics; D007674:Kidney Diseases / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D008099:Liver / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000473:pathology; D009929:Organ Size; D009928:Organ Specificity; D012084:Renin-Angiotensin System / Q000502:physiology*
D000808:Angiotensinogen