Lysozyme enhances renal excretion of advanced glycation endproducts in vivo and suppresses adverse AGE-mediated cellular effects in vitro: A potential AGE sequestration therapy for diabetic nephropathy?

Abstract

Background: Lysozyme (LZ), a host-defense protein, contains an 18 amino-acid domain with high affinity binding for sugar-derived proteins or lipids, called advanced glycation endproducts (AGE), that are implicated in diabetes- and age-dependent complications (DC). Materials and Methods: A) The effects of LZ on AGE-removal were tested in vivo. LZ was injected (200 ug/day, i.p., ×2 weeks) in non-obese diabetic (NOD), db/db (+/+) mice, and non-diabetic, AGE-infused Sprague-Dawley rats. B) LZ: AGE interactions with macrophage-like T1B-183 cells (Mf) and mesangial cells (MC) were tested in vitro. Results: A) In NOD mice, LZ reduced the elevated basal serum AGE (sAGE) (p < 0.05), enhanced urinary AGE (uAGE) excretion by ∼2-fold (p < 0.01), while it reduced albuminuria (UA), p < 0.005. In db/db mice, LZ infusion also reduced the elevated sAGE (p < 0.05), doubled uAGE excretion (p < 0.05), and decreased UA (p < 0.01). In addition, LZ maintained normal sAGE in normal rats infused with AGE-BSA, as it doubled the urinary AGE (uAGE) clearance (p < 0.01). B) LZ stimulated the uptake and degradation of 125I-labeled AGE-BSA and 25I-human serum AGE by Mf, while suppressing AGE-induced TNFα and IGF-I production. In MC, LZ suppressed the AGE-promoted PDGF-B, α1 type IV collagen, and tenascin mRNA levels, and restored the AGE-suppressed expression and activity of MMP-9, but not MMP-2. Conclusion: LZ may act to: a) accelerate renal in-vivo AGE clearance, b) suppress macrophage and mesangial cell-specific gene activation in vitro, and c) improve albuminuria due to diabetes. These data suggest that LZ by sequestering AGEs may protect against diabetic renal damage.