ALTERED KIDNEY MATRIX GENE-EXPRESSION IN EARLY STAGES OF EXPERIMENTALDIABETES

The expression of mRNA and distribution of alpha 1(IV), alpha 3(IV) ch ains of type IV collagen, matrix metalloproteinase 2 (MMP-2), and tiss ue inhibitor of metalloproteinase 1 (TIMP-1) were examined in kidneys from streptozotocin-diabetic rats, 2.5 months after administration of the drug, an early time point when specific diabetic glomerular change s were still minimal. Ten age-matched Sprague-Dawley rats were assigne d to control and diabetic groups. Compared to the controls, the diabet ic rats had a significantly lower body weight, higher kidney weight an d serum glucose levels, but no significant changes of glomerular surfa ce area and urine albumin were observed. Northern blot analysis, using whole kidney mRNA, revealed that diabetic rat kidneys expressed 113.5 % more alpha 1(IV), 46.5% more alpha 3(IV), 54.8% less MMP-2 and 246% more TIMP-1 (in all instances: p<0.05). These results were corroborate d by in situ hybridization for RNA expression. A quantitative analysis of the data indicated the following changes in glomeruli: (1) 74.6% m ore alpha 1(IV), (2) 103.8% more alpha 3(IV), (3) 40.7% less MMP-2 and (4) 80.9% more TIMP-1. Similar changes were observed in tubular (prox imal and distal) cells. We conclude that an increased synthesis and de creased degradation of renal extracellular matrix components occur ear ly after induction of experimental diabetes, before the onset of typic al structural changes in the kidneys, and represent changes of specifi c gene expression at the transcriptional level. All the cell types in the glomerulus as well as the proximal and distal tubules appear to be involved in this alteration of expression, and this is a novel findin g.