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Title: Effects of endothelin or angiotensin II receptor blockade on diabetes in the transgenic (mRen-2)27 rat.
Austin Authors: Kelly, D J;Skinner, S L;Gilbert, Richard E;Cox, Allison J;Cooper, Mark E;Wilkinson-Berka, J L
Affiliation: Department of Medicine, Austin and Repatriation Medical Center, Heidelberg West, and Department of Physiology, University of Melbourne, Parkville, Victoria, Australia
Issue Date: 1-May-2000
Publication information: Kidney International; 57(5): 1882-94
Abstract: Endothelin (ET) and angiotensin II (Ang II) are vasoactive/trophic peptides that may contribute to the progression of diabetic nephropathy. The transgenic (mRen-2)27 rat exhibits overexpression of Ang II at sites of normal physiological expression. Unlike other rat strains, the streptozotocin-induced diabetic Ren-2 rat develops progressive renal pathology associated with a declining glomerular filtration rate (GFR) and provides a convenient model to evaluate the role of these vasoactive peptides in the nephropathic process.Oral administration of either the endothelin A (ETA) and ETB receptor antagonist bosentan or the angiotensin type 1 (AT1) receptor antagonist valsartan for 12 weeks reduced systolic blood pressure (SBP) of nondiabetic and diabetic Ren-2 rats to normotensive levels. Diabetic renal pathology was associated with intense renin mRNA and protein in the proximal tubules and juxtaglomerular cells along with overexpression of transforming growth factor-beta1 (TGF-beta1) and collagen IV mRNA in glomeruli and tubules. With valsartan but not bosentan, renin mRNA and protein in the proximal tubules were not detected. Valsartan but not bosentan reduced TGF-beta1 and collagen IV mRNA and the severity of diabetic renal pathology. A declining GFR with diabetes was attenuated by both treatments. Albuminuria in diabetic rats rose further with bosentan but was reduced with valsartan.Despite producing normotension, severe diabetic renal pathology was not prevented by bosentan, suggesting dissociation of ET, albuminuria, and hypertension from the structural injury in this diabetic model. The beneficial effects afforded by valsartan therapy strengthen the importance of the local renin-angiotensin system in mediating progressive diabetic renal injury.
Gov't Doc #: 10792607
DOI: 10.1046/j.1523-1755.2000.00038.x
Type: Journal Article
Subjects: Angiotensin Receptor Antagonists
Animals, Genetically Modified
Blood Pressure.drug effects
Body Weight
Diabetes Mellitus, Experimental.drug therapy.metabolism.pathology
Diabetic Nephropathies.drug therapy.metabolism.pathology
RNA, Messenger.analysis
Receptor, Angiotensin, Type 1
Receptor, Angiotensin, Type 2
Transforming Growth Factor beta.physiology
Appears in Collections:Journal articles

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