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?
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).


METHODS
A) The effects of LZ on AGE- removal were tested in vivo. LZ was injected (200 ug/day, i.p., X2 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 approximately 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 (125) I-labeled AGE-BSA and (25) I-human serum AGE by Mf, while suppressing AGE-induced TNFalpha and IGF-I production. In MC, LZ suppressed the AGE-promoted PDGF-B, alpha1 type IV collagen, and tenascin mRNA levels, and restored the AGE-suppressed expression and activity of MMP-9, but not MMP-2.


CONCLUSIONS
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.
Zheng
F
F
Division of Experimental Diabetes and Aging, Mount Sinai School of Medicine, New York, NY 10029-6574, USA.
Cai
W
W
Mitsuhashi
T
T
Vlassara
H
H
D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D002645:Chickens; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000378:metabolism*; D005260:Female; D005920:Glomerular Mesangium / Q000378:metabolism / Q000473:pathology; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000652:urine; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008875:Middle Aged; D009113:Muramidase / Q000494:pharmacology*; D051381:Rats
D000890:Anti-Infective Agents; D017127:Glycation End Products, Advanced; D009113:Muramidase