Prevention of diabetic nephropathy in db/db mice with glycated albumin antagonists. A novel treatment strategy

M. P. Cohen, Kumar Sharma, Y. Jin, E. Hud, V. Y. Wu, J. Tomaszewski, F. N. Ziyadeh

Research output: Contribution to journalArticle

133 Citations (Scopus)

Abstract

Accelerated protein glycation in diabetes has been mechanistically linked to the pathogenesis of diabetic nephropathy. Because glycated albumin induces abnormalities in cultured mesangial cells that resemble those characterizing the glomerular mesangium in diabetes, and monoclonal antibodies (A717) specific for Amadori-modified glycated albumin prevent these abnormalities, we postulated that in vivo administration of A717 could retard the progression of diabetic nephropathy. To test this hypothesis, diabetic db/db mice and their nondiabetic db/m littermates were treated with eight consecutive weekly injections of 150 μg of A717 (Fab fragments) to reduce the elevated plasma glycated albumin concentration, or with irrelevant murine IgG (MIg). Relative to nondiabetics, diabetic mice (MIg treated) manifested proteinuria (3.35±0.15 vs 0.87±0.1 mg albumin/mg creatinine), 3.8-fold increase in mesangial matrix fraction, and renal cortical overexpression of mRNAs encoding α1(IV) collagen (2.6-fold increase) and fibronectin (3.8- fold increase). Treatment of db/db mice with A717 significantly reduced the proteinuria (1.52±0.3 mg/mg creatinine), inhibited mesangial matrix expansion, and attenuated overexpression of matrix mRNAs. The nephropathic protective effects of A717 were independent of any change in blood glucose concentrations. Antibodies unreactive with glycated albumin did not duplicate the beneficial effects of A717. Thus, abrogating the biologic effects of increased glycated albumin with A717 has a salutary influence on the pathogenesis of diabetic nephropathy and has novel therapeutic potential in its management.

Original languageEnglish (US)
Pages (from-to)2338-2345
Number of pages8
JournalJournal of Clinical Investigation
Volume95
Issue number5
DOIs
StatePublished - Jan 1 1995
Externally publishedYes

Fingerprint

Diabetic Nephropathies
Proteinuria
Creatinine
Glomerular Mesangium
Immunoglobulin G
Therapeutics
Messenger RNA
Immunoglobulin Fab Fragments
Mesangial Cells
Fibronectins
Serum Albumin
Blood Glucose
Albumins
Cultured Cells
Collagen
Monoclonal Antibodies
glycosylated serum albumin
Kidney
Injections
Antibodies

Keywords

  • albuminuria
  • collagen type IV
  • fibronectin
  • mesangium
  • nonenzymatic glycation

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Prevention of diabetic nephropathy in db/db mice with glycated albumin antagonists. A novel treatment strategy. / Cohen, M. P.; Sharma, Kumar; Jin, Y.; Hud, E.; Wu, V. Y.; Tomaszewski, J.; Ziyadeh, F. N.

In: Journal of Clinical Investigation, Vol. 95, No. 5, 01.01.1995, p. 2338-2345.

Research output: Contribution to journalArticle

Cohen, M. P. ; Sharma, Kumar ; Jin, Y. ; Hud, E. ; Wu, V. Y. ; Tomaszewski, J. ; Ziyadeh, F. N. / Prevention of diabetic nephropathy in db/db mice with glycated albumin antagonists. A novel treatment strategy. In: Journal of Clinical Investigation. 1995 ; Vol. 95, No. 5. pp. 2338-2345.
@article{23892e87168840d3af88662a79c115d2,
title = "Prevention of diabetic nephropathy in db/db mice with glycated albumin antagonists. A novel treatment strategy",
abstract = "Accelerated protein glycation in diabetes has been mechanistically linked to the pathogenesis of diabetic nephropathy. Because glycated albumin induces abnormalities in cultured mesangial cells that resemble those characterizing the glomerular mesangium in diabetes, and monoclonal antibodies (A717) specific for Amadori-modified glycated albumin prevent these abnormalities, we postulated that in vivo administration of A717 could retard the progression of diabetic nephropathy. To test this hypothesis, diabetic db/db mice and their nondiabetic db/m littermates were treated with eight consecutive weekly injections of 150 μg of A717 (Fab fragments) to reduce the elevated plasma glycated albumin concentration, or with irrelevant murine IgG (MIg). Relative to nondiabetics, diabetic mice (MIg treated) manifested proteinuria (3.35±0.15 vs 0.87±0.1 mg albumin/mg creatinine), 3.8-fold increase in mesangial matrix fraction, and renal cortical overexpression of mRNAs encoding α1(IV) collagen (2.6-fold increase) and fibronectin (3.8- fold increase). Treatment of db/db mice with A717 significantly reduced the proteinuria (1.52±0.3 mg/mg creatinine), inhibited mesangial matrix expansion, and attenuated overexpression of matrix mRNAs. The nephropathic protective effects of A717 were independent of any change in blood glucose concentrations. Antibodies unreactive with glycated albumin did not duplicate the beneficial effects of A717. Thus, abrogating the biologic effects of increased glycated albumin with A717 has a salutary influence on the pathogenesis of diabetic nephropathy and has novel therapeutic potential in its management.",
keywords = "albuminuria, collagen type IV, fibronectin, mesangium, nonenzymatic glycation",
author = "Cohen, {M. P.} and Kumar Sharma and Y. Jin and E. Hud and Wu, {V. Y.} and J. Tomaszewski and Ziyadeh, {F. N.}",
year = "1995",
month = "1",
day = "1",
doi = "10.1172/JCI117926",
language = "English (US)",
volume = "95",
pages = "2338--2345",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "5",

}

TY - JOUR

T1 - Prevention of diabetic nephropathy in db/db mice with glycated albumin antagonists. A novel treatment strategy

AU - Cohen, M. P.

AU - Sharma, Kumar

AU - Jin, Y.

AU - Hud, E.

AU - Wu, V. Y.

AU - Tomaszewski, J.

AU - Ziyadeh, F. N.

PY - 1995/1/1

Y1 - 1995/1/1

N2 - Accelerated protein glycation in diabetes has been mechanistically linked to the pathogenesis of diabetic nephropathy. Because glycated albumin induces abnormalities in cultured mesangial cells that resemble those characterizing the glomerular mesangium in diabetes, and monoclonal antibodies (A717) specific for Amadori-modified glycated albumin prevent these abnormalities, we postulated that in vivo administration of A717 could retard the progression of diabetic nephropathy. To test this hypothesis, diabetic db/db mice and their nondiabetic db/m littermates were treated with eight consecutive weekly injections of 150 μg of A717 (Fab fragments) to reduce the elevated plasma glycated albumin concentration, or with irrelevant murine IgG (MIg). Relative to nondiabetics, diabetic mice (MIg treated) manifested proteinuria (3.35±0.15 vs 0.87±0.1 mg albumin/mg creatinine), 3.8-fold increase in mesangial matrix fraction, and renal cortical overexpression of mRNAs encoding α1(IV) collagen (2.6-fold increase) and fibronectin (3.8- fold increase). Treatment of db/db mice with A717 significantly reduced the proteinuria (1.52±0.3 mg/mg creatinine), inhibited mesangial matrix expansion, and attenuated overexpression of matrix mRNAs. The nephropathic protective effects of A717 were independent of any change in blood glucose concentrations. Antibodies unreactive with glycated albumin did not duplicate the beneficial effects of A717. Thus, abrogating the biologic effects of increased glycated albumin with A717 has a salutary influence on the pathogenesis of diabetic nephropathy and has novel therapeutic potential in its management.

AB - Accelerated protein glycation in diabetes has been mechanistically linked to the pathogenesis of diabetic nephropathy. Because glycated albumin induces abnormalities in cultured mesangial cells that resemble those characterizing the glomerular mesangium in diabetes, and monoclonal antibodies (A717) specific for Amadori-modified glycated albumin prevent these abnormalities, we postulated that in vivo administration of A717 could retard the progression of diabetic nephropathy. To test this hypothesis, diabetic db/db mice and their nondiabetic db/m littermates were treated with eight consecutive weekly injections of 150 μg of A717 (Fab fragments) to reduce the elevated plasma glycated albumin concentration, or with irrelevant murine IgG (MIg). Relative to nondiabetics, diabetic mice (MIg treated) manifested proteinuria (3.35±0.15 vs 0.87±0.1 mg albumin/mg creatinine), 3.8-fold increase in mesangial matrix fraction, and renal cortical overexpression of mRNAs encoding α1(IV) collagen (2.6-fold increase) and fibronectin (3.8- fold increase). Treatment of db/db mice with A717 significantly reduced the proteinuria (1.52±0.3 mg/mg creatinine), inhibited mesangial matrix expansion, and attenuated overexpression of matrix mRNAs. The nephropathic protective effects of A717 were independent of any change in blood glucose concentrations. Antibodies unreactive with glycated albumin did not duplicate the beneficial effects of A717. Thus, abrogating the biologic effects of increased glycated albumin with A717 has a salutary influence on the pathogenesis of diabetic nephropathy and has novel therapeutic potential in its management.

KW - albuminuria

KW - collagen type IV

KW - fibronectin

KW - mesangium

KW - nonenzymatic glycation

UR - http://www.scopus.com/inward/record.url?scp=0028903236&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0028903236&partnerID=8YFLogxK

U2 - 10.1172/JCI117926

DO - 10.1172/JCI117926

M3 - Article

C2 - 7738197

AN - SCOPUS:0028903236

VL - 95

SP - 2338

EP - 2345

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 5

ER -