ACTIONS OF HEPATOCYTE GROWTH-FACTOR AS A LOCAL MODULATOR IN THE KIDNEY - POTENTIAL ROLE IN PATHOGENESIS OF RENAL-DISEASE

Endothelial cells are known to secrete various vasoactive substances t hat may control mesangial cell growth, whereas mesangial cells also se crete various growth factors and cytokines that may regulate endotheli al cells. Therefore, it is apparent that cell-cell interactions among renal cells are important in the control of renal function. Indeed, co -culture of endothelial cells with mesangial cells resulted in a signi ficant decrease in mesangial cell growth. However, the exact mechanism s of maintaining the cell-cell interactions are not yet understood. We have focused on the role of hepatocyte growth factor (HGF) in the reg ulation of cell-cell interactions, since HGF has been reported to have many organ protective functions in the kidney. Our present data demon strated that addition of recombinant HGF (rHGF) stimulated DNA synthes is and growth of endothelial cells in a dose-dependent manner. However , there was no stimulatory effect of rHGF on the growth of mesangial c ells in the time and dose-dependent manner. Therefore, we examined the presence of the local renal HGF system and its potential role in rena l disease. The presence of secreted local HGF was observed in the cond itioned medium from endothelial and mesangial cells. The presence of H GF mRNA was also detected in endothelial and mesangial cells. Interest ingly, the specific receptor of HGF, c-met, was also expressed in both cells. Next, regulation of local HGF secretion was studied under stim ulation with rHGF, angiotensin (Ang) II, and transforming growth facto r (TGF)-beta. Of importance, rHGF significantly stimulated local HGF s ecretion from mesangial cells by positive feedback. In contrast, TGF-b eta significantly decreased HGF secretion in mesangial cells and endot helial cells. Angiotensin II also significantly decreased local HGF pr oduction in mesangial cells in a dose-dependent manner. Finally, the e ffect of local HGF production from mesangial cells was studied using a co-culture system. Go-culture of mesangial cells with endothelial cel ls resulted in a significant increase in number of endothelial cells, which was abolished by co-incubation with neutralizing anti-HGF antibo dy. Overall, these results demonstrated the local production of HGF, w hich has stimulatory effects on growth of endothelial cells, but not m esangial cells. Local HGF secretion from mesangial cells may maintain the growth of endothelial cells. Negative regulation of local HGF prod uction by Ang II and TGF-beta may play an important role in the pathog enesis of renal disease. Taken together, dysfunction of cell-cell regu lation in the kidney due to decreased local HGF production may be an i nitial trigger for the development of renal disease such as glomerulon ephritis.