Prevention of renal damage by angiotensin II blockade, accompanied by increased renal hepatocyte growth factor in experimental hypertensive rats

Hepatocyte growth factor (HGF) is a unique growth factor that has many prot ective functions against renal damage. Our previous study demonstrated that HGF stimulated the growth of endothelial and epithelial cells without the replication of mesangial cells. Moreover, angiotensin (Ang) II significantl y decreased local HGF production in mesangial cells. Therefore, we examined the effects of Ang II blockade on renal HGF expression and renal damage in experimental hypertensive rats. An angiotensin-converting enzyme inhibitor (cilazapril; 10 mg . kg(-1) . d(-1)), an Ang II type 1 receptor antagonist (E-4177; 30 mg . kg(-1) . d(-1)), hydralazine (8 mg . kg(-1) . d(-1)), and vehicle were administered to 16-week-old stroke-prone spontaneously hypert ensive rats (SHR-SP) for 3 weeks. Renal damage was evaluated with a compute r analysis system, and renal HGF mRNA was measured by Northern blot analysi s. Blood pressure of SHR-SP was significantly decreased by all drug treatme nts compared with vehicle. Moreover, cilazapril, E-4177, and hydralazine si gnificantly decreased the thickening and necrosis of blood vessels compared with vehicle. Similarly, degeneration and necrosis of glomeruli were also markedly improved by cilazapril and E-4177 (P<0.01), We next examined the e ffects of Ang II blockade on renal HGF expression in SHR-SP, Renal HGF mRNA was markedly decreased in SHR-SP compared with Wistar-Kyoto rats, although Ang II blockade by cilazapril and E-4177 but not hydralazine significantly increased renal HGF mRNA in SHR-SP. Ang II blockade significantly increase d renal HGF (a protective growth factor for tubular epithelial cells); thus , we examined tubular histological appearance. Degeneration and necrosis of tubules were significantly improved by cilazapril and E-4177 treatment (P< 0.01). In addition, cell infiltration into the glomeruli and hemorrhage wer e also significantly reduced in SHR-SP treated with cilazapril or E-4177. T he present data demonstrated the prevention of renal damage by Ang II block ade in SHR-SP, which was accompanied by a significant increase in renal HGF mRNA. Given the strong mitogenic activity and antiapoptotic actions of HGF on endothelial and epithelial cells, we believe that increased local HGF p roduction by the blockade of Ang II may improve renal function in hypertens ion.