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

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

Research output: Contribution to journalArticle

134 Scopus citations

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

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Keywords

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

ASJC Scopus subject areas

  • Medicine(all)

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