Prevention and Reversal of Diabetic Nephropathy in db/db Mice Treated with Alagebrium (ALT-711) (original) (raw)
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Research Articles| December 19 2006
aDepartments of Geriatrics and
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cDepartment of Surgery, Columbia University, New York, N.Y., and
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aDepartments of Geriatrics and
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aDepartments of Geriatrics and
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dDepartment of Pediatrics, University of Minnesota, Minneapolis, Minn., USA
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aDepartments of Geriatrics and
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aDepartments of Geriatrics and
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bMedicine, Mount Sinai School of Medicine, New York, N.Y.,
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Am J Nephrol (2006) 26 (5): 430–436.
Abstract
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 ΕN-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. Conclusion: 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.
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2006
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