THE EXTRACELLULAR-MATRIX IN DIABETIC NEPHROPATHY

In the subgroup of diabetic patients who are destined to develop the full spectrum of the clinical syndrome of diabetic nephropathy, the kidney is afflicted with a series of distinct structural lesions principally involving the extracellular matrices. Diabetic nephropathy is characterized by hypertrophy of both glomerular and tubular elements, progressive accumulation of extracellular matrix components in the glomerular mesangium, and thickening of the glomerular and tubular basement membranes. Albeit less well recognized, progressive tubulointerstitial fibrosis is also a feature of the syndrome. Irrespective of pathogenetic mechanisms (be they metabolic, hemodynamic, or genetic), the structural changes involving the renal extracellular matrix compartments are believed to be the 'basis for the appearance of overt dysfunction, namely, proteinuria, hypertension, and renal failure. Therefore, a full understanding of the mechanisms that culminate in irreversible kidney failure requires a closer inspection of the status of the extracellular matrix in diabetes. This review outlines the different structural changes that typically occur during the course of the disease. Both glomerular and tubulointerstitial changes are reviewed. Valuable structural-functional correlations have been derived from examining kidney specimens obtained from patients with a wide spectrum of disease stages. Experimental animal models, supplanted with recent investigations in tissue culture on the effect of high ambient glucose levels, have increased our understanding of the cellular mechanisms that underlie the disordered matrix composition. Alterations in the metabolism of the collagens, proteoglycans, and other matrix constituents are reviewed. A large body of studies has provided supportive evidence that the changes in the metabolic environment and in the local humoral balance are critical in the genesis of cellular dysfunction and abnormalities in matrix metabolism. In general, the effects of high glucose concentration have been attributed to several metabolic alterations related to nonenzymatic glycation, polyol pathway activation, and disordered myo-inositol metabolism, as well as to changes in humoral responsiveness. Our previous work has demonstrated the similarities between the actions of transforming growth factor-β and those of elevated ambient glucose on cellular growth and extracellular matrix production in cultured renal cells, and we have gathered supportive evidence that transforming growth factor-β may be an important cytokine in mediating diabetic nephropathy. Advances in our knowledge of the cellular mediators of altered growth and extracellular matrix production may provide new insights into more effective and safer therapy to prevent diabetic nephropathy or to intercept its progression. © 1993, National Kidney Foundation. All rights reserved. All rights reserved.