Reactive immunization suppresses advanced glycation and mitigates diabetic nephropathy

Tatiana Shcheglova, Sudesh P Makker, Alfonso Tramontano

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Agents that inhibit glycation end products by reducing the carbonyl load from glycation and glycoxidation are an emerging pharmacologic approach to treat complications of diabetes. We previously demonstrated that antibodies generated to the glycoprotein keyhole limpet hemocyanin (KLH) can cross-link with reactive carbonyl residues on protein conjugates. Here, we immunized streptozotocininduced diabetic rats with KLH to assess the capacity of the elicited antibodies to intercept carbonyl residues on glycated proteins and to mitigate glycation-related pathology. Compared with diabetic rats immunized with adjuvant alone, KLH-immunized diabetic rats had decreased levels of glycated peptides in sera and demonstrated a reduction in albuminuria, proteinuria, deposition of glycation end products in the kidney, and histologic damage. In vitro, low molecular weight glycated peptides from rat serum reacted with anti-KLH antibodies at a faster rate than normal IgG and selectively modified the λ chains. The reaction products contained peptide sequences from type I collagen α chain, albumin, and LDL receptor-related protein. These adduction reactions were inhibited by free KLH and by reduction of glycated peptides with borohydride. In summary, these results suggest that inherent reactivity of Ig light chains provides a natural mechanism for the removal of cytotoxic glycation products. This reactivity can be augmented by glycoprotein-specific reactive immunization, a potential biopharmaceutical approach to glycation-related pathology.

Original languageEnglish (US)
Pages (from-to)1012-1019
Number of pages8
JournalJournal of the American Society of Nephrology
Volume20
Issue number5
DOIs
StatePublished - May 2009

Fingerprint

Diabetic Nephropathies
Immunization
Peptides
Antibodies
Glycoproteins
Low Density Lipoprotein Receptor-Related Protein-1
Pathology
Borohydrides
Albuminuria
Diabetes Complications
Collagen Type I
Serum
Proteinuria
Albumins
Proteins
Immunoglobulin G
Molecular Weight
keyhole-limpet hemocyanin
Kidney
Light

ASJC Scopus subject areas

  • Nephrology
  • Medicine(all)

Cite this

Reactive immunization suppresses advanced glycation and mitigates diabetic nephropathy. / Shcheglova, Tatiana; Makker, Sudesh P; Tramontano, Alfonso.

In: Journal of the American Society of Nephrology, Vol. 20, No. 5, 05.2009, p. 1012-1019.

Research output: Contribution to journalArticle

@article{0bc2988d4eec4dd1badc509c5185a647,
title = "Reactive immunization suppresses advanced glycation and mitigates diabetic nephropathy",
abstract = "Agents that inhibit glycation end products by reducing the carbonyl load from glycation and glycoxidation are an emerging pharmacologic approach to treat complications of diabetes. We previously demonstrated that antibodies generated to the glycoprotein keyhole limpet hemocyanin (KLH) can cross-link with reactive carbonyl residues on protein conjugates. Here, we immunized streptozotocininduced diabetic rats with KLH to assess the capacity of the elicited antibodies to intercept carbonyl residues on glycated proteins and to mitigate glycation-related pathology. Compared with diabetic rats immunized with adjuvant alone, KLH-immunized diabetic rats had decreased levels of glycated peptides in sera and demonstrated a reduction in albuminuria, proteinuria, deposition of glycation end products in the kidney, and histologic damage. In vitro, low molecular weight glycated peptides from rat serum reacted with anti-KLH antibodies at a faster rate than normal IgG and selectively modified the λ chains. The reaction products contained peptide sequences from type I collagen α chain, albumin, and LDL receptor-related protein. These adduction reactions were inhibited by free KLH and by reduction of glycated peptides with borohydride. In summary, these results suggest that inherent reactivity of Ig light chains provides a natural mechanism for the removal of cytotoxic glycation products. This reactivity can be augmented by glycoprotein-specific reactive immunization, a potential biopharmaceutical approach to glycation-related pathology.",
author = "Tatiana Shcheglova and Makker, {Sudesh P} and Alfonso Tramontano",
year = "2009",
month = "5",
doi = "10.1681/ASN.2008050555",
language = "English (US)",
volume = "20",
pages = "1012--1019",
journal = "Journal of the American Society of Nephrology : JASN",
issn = "1046-6673",
publisher = "American Society of Nephrology",
number = "5",

}

TY - JOUR

T1 - Reactive immunization suppresses advanced glycation and mitigates diabetic nephropathy

AU - Shcheglova, Tatiana

AU - Makker, Sudesh P

AU - Tramontano, Alfonso

PY - 2009/5

Y1 - 2009/5

N2 - Agents that inhibit glycation end products by reducing the carbonyl load from glycation and glycoxidation are an emerging pharmacologic approach to treat complications of diabetes. We previously demonstrated that antibodies generated to the glycoprotein keyhole limpet hemocyanin (KLH) can cross-link with reactive carbonyl residues on protein conjugates. Here, we immunized streptozotocininduced diabetic rats with KLH to assess the capacity of the elicited antibodies to intercept carbonyl residues on glycated proteins and to mitigate glycation-related pathology. Compared with diabetic rats immunized with adjuvant alone, KLH-immunized diabetic rats had decreased levels of glycated peptides in sera and demonstrated a reduction in albuminuria, proteinuria, deposition of glycation end products in the kidney, and histologic damage. In vitro, low molecular weight glycated peptides from rat serum reacted with anti-KLH antibodies at a faster rate than normal IgG and selectively modified the λ chains. The reaction products contained peptide sequences from type I collagen α chain, albumin, and LDL receptor-related protein. These adduction reactions were inhibited by free KLH and by reduction of glycated peptides with borohydride. In summary, these results suggest that inherent reactivity of Ig light chains provides a natural mechanism for the removal of cytotoxic glycation products. This reactivity can be augmented by glycoprotein-specific reactive immunization, a potential biopharmaceutical approach to glycation-related pathology.

AB - Agents that inhibit glycation end products by reducing the carbonyl load from glycation and glycoxidation are an emerging pharmacologic approach to treat complications of diabetes. We previously demonstrated that antibodies generated to the glycoprotein keyhole limpet hemocyanin (KLH) can cross-link with reactive carbonyl residues on protein conjugates. Here, we immunized streptozotocininduced diabetic rats with KLH to assess the capacity of the elicited antibodies to intercept carbonyl residues on glycated proteins and to mitigate glycation-related pathology. Compared with diabetic rats immunized with adjuvant alone, KLH-immunized diabetic rats had decreased levels of glycated peptides in sera and demonstrated a reduction in albuminuria, proteinuria, deposition of glycation end products in the kidney, and histologic damage. In vitro, low molecular weight glycated peptides from rat serum reacted with anti-KLH antibodies at a faster rate than normal IgG and selectively modified the λ chains. The reaction products contained peptide sequences from type I collagen α chain, albumin, and LDL receptor-related protein. These adduction reactions were inhibited by free KLH and by reduction of glycated peptides with borohydride. In summary, these results suggest that inherent reactivity of Ig light chains provides a natural mechanism for the removal of cytotoxic glycation products. This reactivity can be augmented by glycoprotein-specific reactive immunization, a potential biopharmaceutical approach to glycation-related pathology.

UR - http://www.scopus.com/inward/record.url?scp=65649118279&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=65649118279&partnerID=8YFLogxK

U2 - 10.1681/ASN.2008050555

DO - 10.1681/ASN.2008050555

M3 - Article

VL - 20

SP - 1012

EP - 1019

JO - Journal of the American Society of Nephrology : JASN

JF - Journal of the American Society of Nephrology : JASN

SN - 1046-6673

IS - 5

ER -