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Effects of Low-Dose and Early versus Late Perindopril Treatment on the Progression of Severe Diabetic Nephropathy in (mREN-2)27 Rats

Sally A. Mifsud^*, Sandford L. Skinner^*, Mark E. Cooper, Darren J. Kelly and Jennifer L. Wilkinson-Berka^*

*Department of Physiology, University of Melbourne, Parkville, Australia; Department of Medicine, Austin and Repatriation Medical Centre, West Heidelberg, Australia; and Department of Medicine, St. Vincent’s Hospital, Fitzroy, Australia.

Correspondence to Dr. Jennifer L. Wilkinson-Berka, Department of Physiology, University of Melbourne, Parkville, Victoria, Australia, 3010. Phone: 61-3-8344-5849; Fax: 61-3-8344-5818; E-mail: j.berka{at}physiology.unimelb.edu.au

ABSTRACT. It was previously reported that transgenic (mRen-2)27 rats with streptozotocin-induced diabetes mellitus progressively develop advanced nephropathy in 12 wk. These lesions are largely prevented when the angiotensin-converting enzyme inhibitor perindopril is administered from the time of induction of diabetes mellitus. This study aimed to determine the lowest dose of early perindopril treatment required for substantial improvement of renal function and structure and to investigate whether late intervention prevents or reverses the progression of established renal lesions. At 6 wk of age, female heterozygous Ren-2 rats were randomized to receive either streptozotocin (diabetic) or citrate buffer (control). Rats were gavaged, beginning early after the induction of diabetes mellitus or the administration of control vehicle, with 0, 0.02, 0.2, or 2 mg/kg per d perindopril for 12 wk. A separate group of diabetic Ren-2 rats received late treatment with 2 mg/kg per d perindopril throughout week 8 to week 12, when rats were hypertensive and albuminuric and exhibited increased kidney weight and glomerulosclerotic index (GSI). Among diabetic rats, early 0.02 mg/kg per d perindopril treatment reduced systolic BP, GSI, and renal collagen staining but had no effect on albuminuria or kidney hypertrophy. Early 0.2 or 2 mg/kg per d perindopril treatment further reduced systolic BP, GSI, and renal collagen staining and decreased albuminuria and kidney hypertrophy. Late intervention was as antihypertensive and antialbuminuric as early 0.2 or 2 mg/kg per d perindopril treatment but did not prevent a moderate increase in GSI. In conclusion, early treatment with 0.2 mg/kg per d perindopril was the lowest dosage to largely prevent severe diabetic nephropathy in transgenic Ren-2 rats. Late-onset perindopril treatment of diabetic rats with established nephropathy was as efficacious as early treatment with respect to various renal parameters, such as albuminuria, but was associated with moderate progression of glomerulosclerosis.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673