RAS blockade decreases blood pressure and proteinuria in transgenic mice overexpressing rat angiotensinogen gene in the kidney.
Angiotensinogen (ANG) is the sole substrate of the renin-angiotensin system (RAS). Clinical studies have shown that RAS activation may lead to hypertension, a major cardiovascular and renal risk factor. To delineate the underlying mechanisms of hypertension-induced nephropathy, we generated transgenic mice that overexpress rat ANG (rANG) in the kidney to establish whether intrarenal RAS activation alone can evoke hypertension and kidney damage and whether RAS blockade can reverse these effects. Transgenic mice overexpressing renal rANG were generated by employing the kidney-specific, androgen-regulated protein promoter linked to rANG cDNA. This promoter targets rANG cDNA to renal proximal tubules and responds to androgen stimulation. Transgenic mice displayed kidney-specific expression of rANG, significantly increased blood pressure (BP) and albuminuria in comparison to non-transgenic littermates. Administration of losartan (an angiotensin II (type 1)-receptor antagonist) or perindopril (an angiotensin-converting enzyme inhibitor) reversed these abnormalities in transgenic animals. Renal injury was evident on examination of the kidneys in transgenic mice, and attenuated by losartan and perindopril treatment. We conclude that the overproduction of ANG alone in the kidney induces an increase in systemic BP, proteinuria, and renal injury. RAS blockers prevent these abnormalities. These data support the role of the intrarenal RAS in the development of hypertension and renal injury.
Sachetelli
S
S
Research Centre, Centre hospitalier de l'Université de Montréal Hôtel-Dieu, Pavillon Masson, Montreal, Quebec, Canada.
Liu
Q
Q
Zhang
S-L
SL
Liu
F
F
Hsieh
T-J
TJ
Brezniceanu
M-L
ML
Guo
D-F
DF
Filep
J G
JG
Ingelfinger
J R
JR
Sigmund
C D
CD
Hamet
P
P
Chan
J S D
JS
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000808:Angiotensinogen / Q000032:analysis* / Q000235:genetics*; D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D015153:Blotting, Western; D018076:DNA, Complementary / Q000032:analysis / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D006973:Hypertension / Q000150:complications / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D007150:Immunohistochemistry; D007668:Kidney / Q000737:chemistry* / Q000503:physiopathology; D007674:Kidney Diseases / Q000209:etiology / Q000503:physiopathology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020913:Perindopril / Q000494:pharmacology; D011506:Proteins / Q000032:analysis / Q000235:genetics; D011507:Proteinuria / Q000503:physiopathology*; D051381:Rats; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology*
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D018076:DNA, Complementary; C067670:Kap protein, mouse; D011506:Proteins; D000808:Angiotensinogen; D019808:Losartan; D020913:Perindopril