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 that may control mesangial cell growth, whereas mesangial cells also secrete various growth factors and cytokines that may regulate endothelial 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 significant decrease in mesangial cell growth. However, the exact mechanisms of maintaining the cell-cell interactions are not yet understood. We have focused on the role of hepatocyte growth factor (HGF) in the regulation of cell-cell interactions, since HGF has been reported to have many organ protective functions in the kidney. Our present data demonstrated that addition of recombinant HGF (rHGF) stimulated DNA synthesis and growth of endothelial cells in a dose-dependent manner. However, there was no stimulatory effect of rHGF on the growth of mesangial cells in the time and dose-dependent manner. Therefore, we examined the presence of the local renal HGF system and its potential role in renal disease. The presence of secreted local HGF was observed in the conditioned medium from endothelial and mesangial cells. The presence of HGF mRNA was also detected in endothelial and mesangial cells. Interestingly, the specific receptor of HGF, c-met, was also expressed in both cells. Next, regulation of local HGF secretion was studied under stimulation with rHGF, angiotensin (Ang) II, and transforming growth factor (TGF)-beta. Of importance, rHGF significantly stimulated local HGF secretion from mesangial cells by positive feedback. In contrast, TGF-beta significantly decreased HGF secretion in mesangial cells and endothelial cells. Angiotensin II also significantly decreased local HGF production in mesangial cells in a dose-dependent manner. Finally, the effect of local HGF production from mesangial cells was studied using a co-culture system. Co-culture of mesangial cells with endothelial cells resulted in a significant increase in number of endothelial cells, which was abolished by co-incubation with neutralizing anti-HGF antibody. Overall, these results demonstrated the local production of HGF, which has stimulatory effects on growth of endothelial cells, but not mesangial cells. Local HGF secretion from mesangial cells may maintain the growth of endothelial cells. Negative regulation of local HGF production by Ang II and TGF-beta may play an important role in the pathogenesis of renal disease. Taken together, dysfunction of cell-cell regulation in the kidney due to decreased local HGF production may be an initial trigger for the development of renal disease such as glomerulonephritis.