DEGRADATION OF EXTRACELLULAR MATRIX IN HUMAN GLOMERULI

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Glomerulosclerosis is characterized by a net accumulation of extracellular matrix components in the glomerulus and results in its progressive obliteration. We started to investigate whether this condition could result from an imbalance between synthesis and degradation of the extracellular matrix. The metalloproteinases which degrade basement membrane collagens are inactivated by a series of inhibitors: TIMPs (tissue inhibitors of metalloproteinases). We examined whether TIMPs mRNAs and the corresponding peptide were expressed in normal and sclerotic glomeruli. We utilized the non tumoral part of nephrectomies performed for cancer in a series of 10 adult patients. The glomeruli were microdissected and reverse-transcribed in situ. Competitive polymerase chain reaction was performed for TIMP I and II mRNAs. Both were detected in the glomeruli and were increased in the specimens in which glomerulosclerosis was present. The increase was not due to an increase in the number of cells in the glomeruli with sclerosis. These data suggest that TIMPs are increased on a per cell basis in the glomerulosclerosis associated with carcinoma. Further studies are in progress to determine whether this increase is also observed in other forms of human glomerulosclerosis. We have also obtained preliminary data indicating that mRNA coding for the 72kd metalloproteinase is expressed in human glomeruli. This species appears to undergo the same upregulation than the alpha-2 chain of type IV collagen.