Renal tubular basement membrane and collagen type IV in diabetes mellitus

Ziyadeh, Fuad N.
January 1993
Kidney International;Jan1993, Vol. 43 Issue 1, p114
Academic Journal
The pathogenesis of the multiple structural lesions in diabetic nephropathy remains debated, and likely is multifactorial. The uniform thickening of the renal basement membranes lining the glomerular and tubular elements appears to be a consequence of the metabolic perturbations which are directly related to hyperglycemia. While most investigations have focused on the increased accumulation of extracellular matrix in the glomerular basement membrane and the mesangium, and their relation to derangements in glomerular function, little is known regarding the pathogenesis and the significance of the tubulointerstitial changes and the thickened tubular basement membrane (TBM). It is possible that these latter changes are causally related to the cellular hypertrophy of the renal tubular epithelium that lines the TBM. It has been postulated that in the earlier stages of the disease, hyperglycemia induces renal tubular hypertrophy and stimulates the synthesis of the various matrix components which are normal constituents of the TBM. Later, the structural composition of the TBM is susceptible to further modifications by non-enzymatic glycation, and this aberrant process may impart a relative resistance to matrix degradation leading to a slow turnover. In vitro investigations on routine proximal tubule cells in culture have provided evidence that elevated ambient glucose is a sufficient stimulus for cellular hypertrophy and increased biosynthesis of collagen type IV, the predominant constituent of TBM. High glucose levels increase steady-state collagen IV mRNA, partly due to transcriptional activation of cis-acting elements of the gene which are controlled by putative glucose-responsive trans-acting proteins. This effect of hyperglycemia may be the consequence of increased activity of the polyol pathway, with attendant alterations in cellular myo-inositol metabolism. Treatment with sorbinil, an aldose reductase inhibitor, or supplementation of the medium with supra-physiologic levels of myo-inositol, prevents the stimulation by high glucose of the increased secretion and biosynthesis of collagen IV. The glucose-induced cellular hypertrophy, however, is minimally affected by these maneuvers, and may result from activation of humoral or local mediators including transforming growth factor-β.


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