TY - JOUR
T1 - Effects of endothelin or angiotensin II receptor blockade on diabetes in the transgenic (mRen-2)27 rat
AU - Kelly, Darren J.
AU - Skinner, Sandford L.
AU - Gilbert, Richard E.
AU - Cox, Alison J.
AU - Cooper, Mark E.
AU - Wilkinson-Berka, Jennifer L.
PY - 2000
Y1 - 2000
N2 - Background. 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. Methods and Results. Oral administration of either the endothelin A (ET(A)) and ET(B) 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 fact or-β1 (TGF-β1) 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-β1 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. Conclusions. 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.
AB - Background. 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. Methods and Results. Oral administration of either the endothelin A (ET(A)) and ET(B) 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 fact or-β1 (TGF-β1) 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-β1 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. Conclusions. 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.
KW - Diabetic nephropathy
KW - Endothelin
KW - Glomerulosclerosis
KW - Hypertension
KW - Renin-angiotensin system
UR - http://www.scopus.com/inward/record.url?scp=0034021275&partnerID=8YFLogxK
U2 - 10.1046/j.1523-1755.2000.00038.x
DO - 10.1046/j.1523-1755.2000.00038.x
M3 - Article
C2 - 10792607
AN - SCOPUS:0034021275
VL - 57
SP - 1882
EP - 1894
JO - Kidney International
JF - Kidney International
SN - 0085-2538
IS - 5
ER -