COLLAGEN COL4A3 KNOCKOUT - A MOUSE MODEL FOR AUTOSOMAL ALPORT SYNDROME

A mouse model for the autosomal form of Alport syndrome was produced. These mice develop a progressive glomerulonephritis with microhematuri a and proteinuria, consistent with the human disease. End-stage renal. disease develops at similar to 14 weeks of age. TEM analysis of the g lomerular basement membranes (GEM) during development of renal patholo gy revealed focal multilaminated thickening and thinning beginning in the external capillary loops at 4 weeks and spreading throughout the G EM by 8 weeks. By 14 weeks, half of the glomeruli were fibrotic with c ollapsed capillaries. Immunofluorescence analysis of the GBM showed th e absence of type IV collagen alpha-3, alpha-4, and alpha-5 chains and a persistence of alpha-1 and alpha-2 chains (these chains normally lo calize to the mesangial matrix). Northern blot analysis using probes s pecific for the collagen chains illustrate the absence of COL4A3 in th e knockout, whereas mRNAs for the remaining chains are unchanged. An a ccumulation of fibronectin, heparan sulfate proteoglycan, laminin-1, a nd entactin was observed in the GBM of the affected animals. The tempo ral and spatial pattern of accumulation was consistent with that for t hickening of the GBM as observed by TEM. Thus, expression of these bas ement membrane-associated proteins may be involved in the progression of Alport renal disease pathogenesis. The levels of mRNAs encoding the basement membrane-associated proteins at 7 weeks were unchanged.