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Attenuation of Interstitial Fibrosis and Tubular Apoptosis in db/db Transgenic Mice Overexpressing Catalase in Renal Proximal Tubular Cells

*Université de Montréal, Centre hospitalier de l'Université de Montréal (CHUM) -Hôtel-Dieu, Research Centre, Pavillon Masson, 3850 Saint Urbain Street, Montreal, Quebec, Canada H2W 1T8
** Université de Montréal, Maisonneuve-Rosemont Hospital, Research Centre, 5415 boul. de l'Assomption, Montreal, Quebec, Canada H1T 2M4
***Harvard Medical School, Massachusetts General Hospital, Pediatric Nephrology Unit, 15 Parkman Street, WAC 709, Boston, MA 02114-3117, USA

Objective: The present study investigated the relationship 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).

Research Design and Methods: Blood pressure, blood glucose and albuminuria were monitored for up to 5 months. Kidneys were processed for histology and apoptosis studies [terminal transferase-deoxyuridine triphosphate nick end-labeling or immunostaining for active caspase-3 and Bax]. Real time-quantitative polymerase chain reaction 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 as compared to db/db mice. Kidneys from db/db mice displayed progressive glomerular hypertrophy, glomerulosclerosis, interstitial fibrosis, 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.

Conclusion: Our results indicate a crucial role for intrarenal 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.

Key Words: Catalase • transgenic mice • db/db mice • tubular apoptosis • diabetes

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