(1) to analyze the glomerular distribution of extracellular matrix (ECM)
antigens at the early stage of DMS, (2) to determine the composition of the ECM accumulated within the mesangial areas and leading to glomerular
sclerosis, and (3) to analyze the expression of
growth factors, transforming growth factor-beta 1 (
TGF beta 1) and
platelet-derived growth factor A (PDGFA). In glomeruli of patients with IDMS and DDS, the glomerular basement membrane (GBM) expression of the
heparan sulfate chain of
heparan sulfate proteoglycan (
HSPG) was decreased from the early stage of DMS, at a time when ECM
proteins retained a normal distribution. In fully developed lesions, mesangial and subendothelial accumulation of collagenous and noncollagenous
glycoproteins normally expressed in the mesangial area (types IV [alpha 1(IV)2 alpha 2(IV)] and VI
collagen, beta 1
laminin,
fibronectin,
tenascin, and
perlecan) increased with progression of mesangial
sclerosis. This was associated with mesangial expression of
proteins normally restricted to the GBM (
agrin, alpha 1/alpha 5, beta 2, and gamma 1
laminin chains) and with accumulation of
chondroitin sulfate proteoglycan. The distribution of the alpha 3-alpha 5 chains of
type IV collagen was normal. Focal accumulation of types I, III, and V
collagen was seen only in severely sclerotic glomeruli. Expression of
growth factors TGF beta 1 and PDGFA was increased in 9 of 10 and 5 of 10 patients, respectively. Early decreased GBM expression of the
heparan sulfate chain of
HSPG could play a role in the
proteinuria of DMS patients. Changes in the composition of the ECM accumulated within the mesangial areas are not specific. We speculate that deregulation of the expression of
growth factors normally downregulated by WT1, is one of the factors responsible for the rapid and massive mesangial deposition of basement membrane material in DDS.