Increased glomerular matrix metalloproteinase activity in murine lupus nephritis

Lupus nephritis is associated with thickening of the glomerular basement membrane. Here we measured expression of proteins involved in extracellular matrix turnover in kidneys of lupus-prone mice of the NZBxNZW F1 (B/W) strain before the onset of the disease until the development of proteinuria. Expression of the major isoforms of glomerular basement collagen IV (alpha 3/alpha 4/alpha 5) was unchanged throughout disease progression. Collagen IV alpha 1 and alpha 2, however, were highly upregulated at the proteinuric stage while collagen IV alpha 6 was increased at all time points compared to normal mice. There was increased expression of matrix metalloproteinase-2 and -9, their protein inhibitors TIMP-1 and -2 and the metalloproteinase-9 stabilizing protein lipocalin-2 in kidneys of nephritic lupus-prone mice. When proteinuria appeared we found an increased net glomerular gelatinolytic activity. These studies suggest that matrix metalloproteinases contribute to extracellular matrix expansion and proteinuria by altering matrix composition.