HYPEROSMOLALITY SUPPRESSES BUT TGF-BETA-1 INCREASES MMP9 IN HUMAN PERITONEAL MESOTHELIAL CELLS

Peritoneal mesothelial cells are directly exposed to hyperosmolar dial ysates which may enhance extracellular matrix accumulation and hence c ompromise ultrafiltration. Because these cells are laid on a type IV c ollagen containing basement membrane, we examined the pattern of type IV collagenases produced by cultured human mesothelial cells and their regulation by hyperosmolality and TGF beta 1. A cell line (HMrSV5) ex hibiting major features of normal peritoneal mesothelial cells was der ived from a primary culture retrovirally transduced with SV40 large-T antigen. Zymography and Western blot analysis showed that: (i) human p eritoneal mesothelial cells produced and excreted MMP2 and MMP9 and th eir inhibitors TIMP1 and TIMP2; (ii) hyperosmolality drastically reduc ed the expression of MMP9 irrespective of the osmolyte used in a time- and concentration-dependent manner; (iii) TGF beta 1 unexpectedly inc reased MMP9 activity and protein in exponentially growing cells and co uld restore MMP9 activity suppressed by hyperosmolality in confluent c ultures. To exclude a specific effect of SV40 large-T antigen on matri x metalloproteinases production and regulation, these results were con firmed in primary cultures derived from visceral peritoneal samples fr om different donors. Therefore, the hyperosmolality of dialysates may favor an accumulation of type IV collagen and thickening of peritoneal basement membrane, while TGF beta 1 released during infections may in duce the degradation of type IV collagen and its replacement by inters titial collagens.