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312 ROLE OF METHYLGLYOXAL IN THE PATHOGENESIS OF DIABETIC NEPHROPATHY.
  1. P. Chuang,
  2. M. A. Saleem,
  3. P. W. Mathieson,
  4. B. G. Hudson,
  5. P. A. Voziyan
  1. Vanderbilt University Medical Center, Nashville, TN

Abstract

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease in the United States. Why DN develops in up to 40% of diabetic patients is currently unknown. Elucidating the underlying mechanisms leading to the development of DN would provide the basis for the design of new therapies to prevent this diabetic complication. One hypothesis on why DN develops implicates the increased formation of a heterogeneous group of compounds collectively called advanced glycation end products (AGEs) in response to chronic hyperglycemia as a possible culprit. Methylglyoxal (MGO), a highly reactive carbonyl compound that is derived from autoxidation of glucose and the degradation of triose phosphates, is elevated in diabetic patients and is a major source of AGEs. We hypothesized that MGO may contribute to the pathogenesis of DN by two mechanisms: (1) by modifying key components that make up the extracellular matrix (ECM) and thus altering the interaction of glomerular kidney cells with the ECM proteins and (2) by having direct toxic effects on these cells leading to decreased cell viability and increased apoptosis. To test the first hypothesis, we coated plates with collagen IV and laminin 1, major components of the renal ECM, and incubated the plates with or without MGO. We found that the adhesion of both immortalized human podocytes and murine mesangial cells to collagen IV and laminin 1 was significantly impaired after these ECM components were modified by MGO. The weakening of the cell-ECM interactions may facilitate the migration and proliferation of mesangial cells leading to increased mesangial matrix, as well as the effacement of the podocyte foot processes and podocyte shedding, common findings in DN. To test whether MGO may also have direct toxic effects on glomerular cells, we incubated the same cells in media with and without MGO. Using cell viability reagent WST-1, we found that MGO led to decreased viability of both podocytes and mesangial cells. MGO also caused apoptosis in both cell types as determined in an ELISA apoptosis assay. Recently, we and other investigators have demonstrated that pyridoxamine (PM) can form covalent adducts with low-molecular-weight carbonyl compounds such as MGO and thereby may potentially protect cells from the toxic effects of MGO. Indeed, when added to glomerular cells PM improved viability of MGO-treated cells and decreased apoptotic cell death. In summary, our results suggest that MGO may contribute to the pathogenesis of DN by direct toxic effects on the glomerular cells and by modifying the underlying ECM. In addition, we found that PM may counteract this MGO toxicity indicating a potential therapeutic mechanism of PM in DN.

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