Attenuation of interstitial fibrosis and tubular apoptosis in db/db transgenic mice overexpressing catalase in renal proximal tubular cells.
OBJECTIVE
The present study investigated the relationships between reactive oxygen species (ROS), interstitial fibrosis, and renal proximal tubular cell (RPTC) apoptosis in type 2 diabetic db/db mice and in db/db transgenic (Tg) mice overexpressing rat catalase (rCAT) in their RPTCs (db/db rCAT-Tg).


METHODS
Blood pressure, blood glucose, and albuminuria were monitored for up to 5 months. Kidneys were processed for histology and apoptosis studies (terminal transferase-mediated dUTP nick-end labeling or immunostaining for active caspase-3 and Bax). Real-time quantitative PCR assays were used to quantify angiotensinogen (ANG), p53, and Bax mRNA levels.


RESULTS
db/db mice developed obesity, hyperglycemia, hypertension, and albuminuria. In contrast, db/db rCAT-Tg mice became obese and hyperglycemic but had normal blood pressure and attenuated albuminuria compared with db/db mice. Kidneys from db/db mice displayed progressive glomerular hypertrophy, glomerulosclerosis, interstitial fibrosis, and tubular apoptosis and increased expression of collagen type IV, Bax, and active caspase-3, as well as increased ROS production. These changes, except glomerular hypertrophy, were markedly attenuated in kidneys of db/db rCAT-Tg mice. Furthermore, ANG, p53, and Bax mRNA expression was increased in renal proximal tubules of db/db mice but not of db/db rCAT-Tg mice.


CONCLUSIONS
Our results indicate a crucial role for intra-renal ROS in the progression of hypertension, albuminuria, interstitial fibrosis, and tubular apoptosis in type 2 diabetes and demonstrate the beneficial effects of suppressing ROS formation.
Brezniceanu
Marie-Luise
ML
Université de Montréal, Centre hospitalier de l'Université de Montréal (CHUM) Hôtel-Dieu, Research Centre, Pavillon Masson, 3850 Saint Urbain St., Montreal, Quebec, Canada.
Liu
Fang
F
Wei
Chih-Chang
CC
Chénier
Isabelle
I
Godin
Nicolas
N
Zhang
Shao-Ling
SL
Filep
Janos G
JG
Ingelfinger
Julie R
JR
Chan
John S D
JS
D000818:Animals; D017209:Apoptosis; D002374:Catalase / Q000235:genetics* / Q000378:metabolism; D002417:Cattle; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology*; D003928:Diabetic Nephropathies; D020287:In Situ Nick-End Labeling; D007687:Kidney Tubules, Proximal / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009395:Nephritis, Interstitial / Q000201:enzymology / Q000235:genetics*; D009765:Obesity / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism
D017382:Reactive Oxygen Species; D002374:Catalase