TY - JOUR
T1 - Renal accumulation and clearance of advanced glycation end-products in type 2 diabetic nephropathy
T2 - Effect of angiotensin-converting enzyme and vasopeptidase inhibition
AU - Wihler, C.
AU - Schäfer, S.
AU - Schmid, K.
AU - Deemer, E. K.
AU - Münch, G.
AU - Bleich, M.
AU - Busch, A. E.
AU - Dingermann, T.
AU - Somoza, V.
AU - Baynes, J. W.
AU - Huber, J.
PY - 2005/8
Y1 - 2005/8
N2 - Aims/hypothesis: Renal accumulation of AGEs may contribute to the progression of diabetic nephropathy. We evaluated the effect of ramipril (a pure ACE inhibitor) and AVE7688 (a dual inhibitor of ACE and neutral endopeptidase) on renal accumulation of the advanced glycation end-product (AGE) 3-deoxyglucosone-imidazolone, carboxymethyllysine (CML) and pentosidine, and on clearance of CML in type 2 diabetes. Methods: Male Zucker diabetic fatty rats (ZDF, Gmi-fa/fa) rats were treated from age 10 to 37 weeks with ramipril (1 mg·kg-1·day-1), AVE7688 (45 mg·kg-1·day-1) or without drug. Ramipril and AVE7688 reduced albuminuria by 30 and 90%, respectively. Results: ZDF rats showed increased renal accumulation of the AGE subtypes 3-deoxyglucosone- imidazolone, pentosidine and CML by about 40, 55 and 55%, respectively compared with heterozygous, non-diabetic control animals at the age of 37 weeks. AVE7688 but not ramipril attenuated the renal accumulation of 3-deoxyglucosone- imidazolone, pentosidine and CML and improved CML clearance in ZDF rats. During glycation reactions in vitro, AVE7688 also demonstrated potent chelating activity and inhibited metal-catalysed formation of pentosidine and CML. Conclusions/interpretation: Improved AGE clearance and direct inhibition of AGE formation by chelation may contribute to reduced accumulation of renal AGEs and to the nephroprotective effects of vasopeptidase inhibition in type 2 diabetes.
AB - Aims/hypothesis: Renal accumulation of AGEs may contribute to the progression of diabetic nephropathy. We evaluated the effect of ramipril (a pure ACE inhibitor) and AVE7688 (a dual inhibitor of ACE and neutral endopeptidase) on renal accumulation of the advanced glycation end-product (AGE) 3-deoxyglucosone-imidazolone, carboxymethyllysine (CML) and pentosidine, and on clearance of CML in type 2 diabetes. Methods: Male Zucker diabetic fatty rats (ZDF, Gmi-fa/fa) rats were treated from age 10 to 37 weeks with ramipril (1 mg·kg-1·day-1), AVE7688 (45 mg·kg-1·day-1) or without drug. Ramipril and AVE7688 reduced albuminuria by 30 and 90%, respectively. Results: ZDF rats showed increased renal accumulation of the AGE subtypes 3-deoxyglucosone- imidazolone, pentosidine and CML by about 40, 55 and 55%, respectively compared with heterozygous, non-diabetic control animals at the age of 37 weeks. AVE7688 but not ramipril attenuated the renal accumulation of 3-deoxyglucosone- imidazolone, pentosidine and CML and improved CML clearance in ZDF rats. During glycation reactions in vitro, AVE7688 also demonstrated potent chelating activity and inhibited metal-catalysed formation of pentosidine and CML. Conclusions/interpretation: Improved AGE clearance and direct inhibition of AGE formation by chelation may contribute to reduced accumulation of renal AGEs and to the nephroprotective effects of vasopeptidase inhibition in type 2 diabetes.
KW - AVE7688
KW - Advanced glycation end-products
KW - Angiotensin-converting enzyme inhibition
KW - Diabetes mellitus
KW - Diabetic nephropathy
KW - Ramipril
KW - Vasopeptidase inhibition
KW - Zucker diabetic fatty rat
UR - http://www.scopus.com/inward/record.url?scp=23844515460&partnerID=8YFLogxK
U2 - 10.1007/s00125-005-1837-9
DO - 10.1007/s00125-005-1837-9
M3 - Article
C2 - 16010524
AN - SCOPUS:23844515460
SN - 0012-186X
VL - 48
SP - 1645
EP - 1653
JO - Diabetologia
JF - Diabetologia
IS - 8
ER -
