PEXICRINE EFFECTS OF BASEMENT-MEMBRANE COMPONENTS ON PARACRINE SIGNALING BY RENAL TUBULAR CELLS

Paracrine interactions between tubular epithelium and interstitial cel ls have been assumed to be mediated largely by soluble cytokines. Whil e the role of extracellular matrix (ECM) and matrix metalloproteinases (MMPs) in modifying cell function is widely appreciated, the role of the renal tubular basement membrane in modulation of tubulointerstitia l function has not been studied. To establish whether those components of the ECM which support tubular epithelial cells also influence cell function (that is, a pexicrine effect), we studied their effects on p aracrine signaling between epithelium and fibroblasts. Primary culture s of rat renal proximal tubular epithelial cells (PTE) were cultured o n laminin (LN), collagen types -IV and I (COL-IV, COL-I) and fibronect in (FN). PTE attained confluence more rapidly when grown on LN = COL-I V > COL-I = FN = plastic. On all substrates PTE produced the MMPs, gel atinase-A and -B and collagenase with an apparent increase in gelatina se-A and -B production when cultured on LN. MMPs were found to be secr eted both apically and basally with basal secretion predominating, exc ept on LN where secretion was primarily from the apical surface. Cultu res of rat renal cortical interstitial fibroblasts were established an d characterized. Cortical fibroblasts (CF) were found to secrete gelat inase-A and collagenase. Conditioned medium (CM) from PTE cultured on COL-IV stimulated proliferation of CF but proliferation was unaltered by CM from PTE grown on other substrates. By contrast, co-culture of P TE on LN with CF suppressed collagenase and gelatinase activity in bot h cell types, indicating a bi-directional, paracrine modulation of MMP production. Thus in the tubulointerstitium, the BM components LN and COL-IV not only fulfill a structural role but act as signaling molecul es with differantial effects which modify the function of the tubular epithelium and its paracrine interaction with adjacent fibroblasts. Th e initiation of interstitial fibrosis induced by injury to the tubular basement membrane may reside in the perturbation of this interaction.