Catalase overexpression prevents hypertension and tubular apoptosis in angiotensinogen transgenic mice.
Transgenic mice that overexpress angiotensinogen, the sole precursor of angiotensins, in their renal proximal tubular cells develop hypertension, albuminuria, and tubular apoptosis. These pathological changes are due to enhanced generation of reactive oxygen species in the proximal tubule cells. Here, we determined whether overexpression of catalase to decrease oxidant injury in the proximal tubular cells could reverse these abnormalities. Double-transgenic mice specifically overexpressing angiotensinogen and catalase in their renal proximal tubular cells were created by cross-breeding the single transgenics. Non-transgenic littermates served as controls. Overexpression of catalase prevented hypertension, albuminuria, tubulointerstitial fibrosis, and tubular apoptosis in the angiotensinogen transgenic mice. Furthermore, the double transgenics had lower reactive oxygen species generation and reduced pro-fibrotic and apoptotic gene expression in the renal proximal tubular cells. Renal angiotensin converting enzyme-2 expression and urinary angiotensin 1-7 levels were downregulated in the single but normal in the double-transgenic mice. Thus, we suggest that the intrarenal renin-angiotensin system and reactive oxygen species generation have an important role in the development of hypertension and renal injury.
Godin
Nicolas
N
Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Hôtel-Dieu Hospital, Pavillon Masson, Montreal, Quebec, Canada H2W 1T8.
Liu
Fang
F
Lau
Garnet J
GJ
Brezniceanu
Marie-Luise
ML
Chénier
Isabelle
I
Filep
Janos G
JG
Ingelfinger
Julie R
JR
Zhang
Shao-Ling
SL
Chan
John S D
JS
D000808:Angiotensinogen / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002374:Catalase / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use; D015870:Gene Expression; D006973:Hypertension / Q000209:etiology / Q000517:prevention & control*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D017382:Reactive Oxygen Species / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000502:physiology
D017382:Reactive Oxygen Species; D000808:Angiotensinogen; D002374:Catalase