Prevention and Reversal of Diabetic Nephropathy in db/db Mice Treated with Alagebrium (ALT-711)

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.

Combination Therapy with the Advanced Glycation End Product Cross-Link Breaker, Alagebrium, and Angiotensin Converting Enzyme Inhibitors in Diabetes: Synergy or Redundancy?

“…These findings also raise the possibility that intracellular superoxide generation may be occurring as a result of an external AGE-dependent stimulus such as the interaction between circulating AGEs and the RAGE receptor. This concept is also supported by the amelioration of serum AGE levels with alagebrium alone, as seen in a recent study (33) or in combination with ramipril. This generation of intracellular superoxide via the AGE-RAGE interaction has been demonstrated previously (38,39).…”

Uremic Toxicity of Advanced Glycation End Products in CKD

“…207) have been shown to improve arterial compliance in humans. 208 Animal and human studies have shown that AGE cross-link breakers, such as ALT-711 and alagebrium, decrease AGE levels 209,210 and tissue AGEs, 211,212 reverse their effects, [213][214][215][216] such as aortic stiffness, calcification, 195 and extracellular matrix accumulation, 212 and improve renal function by facilitating urinary excretion of the end products. (Table 1).…”

Nε-(carboxymethyl) lysine-induced mitochondrial fission and mitophagy cause decreased insulin secretion from β-cells

“…AGEs may impair insulin secretion and lead to the development of diabetes (7). A previous report showed that serum levels of N ε -(carboxymethyl) lysine-conjugated AGEs, a major constituent of AGEs, were elevated up to 42-44 U/ml in 7-mo-old db/db mice (29). AGEs are important inducers of intracellulargenerated reactive oxygen species (ROS), which are produced mainly by NADPH oxidase and the mitochondrial respiratory chain system (13).…”