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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?

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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.

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Acknowledgments

This work was supported in part by an NIH grant (DK57126) and a program project grant from the Juvenile Diabetes Research Foundation (JDRF-4-1999-697). We thank Ms. Ina Katz for invaluable editorial assistance and Dr. Michael A. Yamin for critically reviewing this manuscript.

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Authors and Affiliations

  1. Division of Experimental Diabetes and Aging, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1640, New York, NY, 10029-6574, USA

    Feng Zheng, Weijing Cai, Tomoko Mitsuhashi & Helen Vlassara

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  1. Feng Zheng
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  2. Weijing Cai
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  4. Helen Vlassara
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  5. R. Bucala
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Correspondence to Helen Vlassara.

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Contributed by R. Bucala.

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Zheng, F., Cai, W., Mitsuhashi, T. et al. 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?. Mol Med 7, 737–747 (2001). https://doi.org/10.1007/BF03401963

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