Prevention and reversal of diabetic nephropathy in db/db mice treated with alagebrium (ALT-711).
BACKGROUND
Alagebrium (ALT-711) has been shown to improve renal dysfunction in animal models of diabetes.


METHODS
To test its effects in diabetic nephropathy (DN), ALT-711 was administered (1 mg/kg daily i.p.) to 9-week-old female db/db mice (n = 15, group A1) for 3 weeks and to 3-month-old (n = 15, group A2), 7-month-old (n = 7, group A3), and 12-month-old (n = 5, group A4) female db/db mice for 12 weeks, while a similar number of diabetic and nondiabetic mice were used as controls. The epsilonN-carboxymethyllysine (CML) levels in serum, urine, skin, and kidney tissue were measured by enzyme-linked immunosorbent assay. The renal morphometric parameters were assessed by electron and light microscopy.


RESULTS
By the 3rd week of treatment, the serum CML level decreased by 41%, and the urinary CML concentration increased by 138% from baseline, while the urinary albumin/creatinine ratio was lower (p < 0.05) in diabetic and nondiabetic group A1 mice. After 3 months of treatment, serum, skin, and kidney CML levels and urinary albumin/creatinine ratio were lower (p < 0.05) and the urinary CML levels higher (p < 0.05) in treated group A2, A3, and A4 animals compared with groups which received phosphate-buffered saline, with a similar pattern observed in nondiabetic mice. The renal morphological parameters characteristic of DN decreased in treated compared with untreated mice.


CONCLUSIONS
Alagebrium may prevent, delay, and/or reverse established DN in db/db mice by reducing the systemic advanced glycation end product pools and facilitating the urinary excretion of advanced glycation end products.
Peppa
Melpomeni
M
Department of Geriatrics, Mount Sinai School of Medicine, New York, NY, USA. moly.peppa@internet.gr
Brem
Harold
H
Cai
Weijing
W
Zhang
Jiang-Gang
JG
Basgen
John
J
Li
Zhu
Z
Vlassara
Helen
H
Uribarri
Jaime
J
D000818:Animals; D003928:Diabetic Nephropathies / Q000097:blood / Q000188:drug therapy* / Q000517:prevention & control*; D005260:Female; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors / Q000097:blood; D008239:Lysine / Q000031:analogs & derivatives / Q000097:blood; D051379:Mice; D008817:Mice, Mutant Strains; D013844:Thiazoles / Q000008:administration & dosage / Q000627:therapeutic use*
D017127:Glycation End Products, Advanced; D013844:Thiazoles; C048496:N(6)-carboxymethyllysine; C406794:alagebrium; D008239:Lysine