CHARACTERISTIC MATRIX AND TUBULAR BASEMENT-MEMBRANE ABNORMALITIES IN THE CBA CA-KDKD MOUSE MODEL OF HEREDITARY TUBULOINTERSTITIAL DISEASE/

CBA/CaH-kdkd mice develop hereditary tubulointerstitial disease with m ononuclear cell infiltration and cyst formation, possibly representing a model of human nephronophthisis. The purpose of the present investi gation was to examine the components of the fibrotic changes which typ ically develop in the kidneys of these mice. By conventional histology , kdkd mice displayed progressive interstitial fibroblast and matrix a ccumulation. Immunohistological analysis of kdkd kidneys showed marked deposition of fibronectin in the tubulointerstitial space and reveale d prominent irregularities for laminin and collagen type IV in the tub ular basement membrane (TBM), including thickening, widening and foldi ng. Electron microscopy confirmed the TBM abnormalities and showed mar ked undulation and thickening in areas of proximal tubular (PT) degene ration. Immunofluorescence staining analysis for the fibronectin recep tors VLA-4 and VLA-5 showed no expression on injured proximal tubules, whereas the expression of the laminin receptor VLA-6 was increased an d irregular on altered PT. Analysis of RNA derived from kdkd kidneys r evealed marked upregulation of steady-state mRNA levels for the fibrog enic growth factor TGF-beta. We conclude that TBM alterations, matrix accumulation and changes in integrin expression together with enhanced TGF-beta production are typical features of kdkd tubulointerstitial d isease and suggest that characteristic TBM or matrix alterations could contribute to the pathogenesis of the disease in these mice.