Effects of endothelin or angiotensin II receptor blockade on diabetes in the transgenic (mRen-2)27 rat

Background. Endothelin (ET) and angiotensin II (Ang II) are vasoactive/trop hic 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 streptozo tocin-induced diabetic Ren-2 rat develops progressive renal pathology assoc iated with a declining glomerular filtration rate (GFR) and provides a conv enient model to evaluate the role of these vasoactive peptides in the nephr opathic process. Methods and Results. Oral administration of either the endothelin A (ETA) a nd ETB receptor antagonist bosentan or the angiotensin type 1 (AT(1)) recep tor antagonist valsartan for 12 weeks reduced systolic blood pressure (SBP) of nondiabetic and diabetic Ren-2 rats to normotensive levels. Diabetic re nal pathology was associated with intense renin mRNA and protein in the pro ximal tubules and juxtaglomerular cells along with overexpression of transf orming growth factor-beta 1 (TGF-beta 1) 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 -beta 1 and collagen IV mRNA and the severity of diabetic renal pathology. A declining GFR with diabetes was attenuated by both treatments. Albuminuri a in diabetic rats rose further with bosentan but was reduced with valsarta n. Conclusions. Despite producing normotension, severe diabetic renal patholog y was not prevented by bosentan, suggesting dissociation of ET, albuminuria , and hypertension from the structural injury in this diabetic model. The b eneficial effects afforded by valsartan therapy strengthen the importance o f the local renin-angiotensin system in mediating progressive diabetic rena l injury.