title: Hepatocyte growth factor induces an endothelin-mediated decline in glomerular filtration rate.
abstract: Hepatocyte growth factor (HGF) is a multifunctional cytokine that plays a crucial role in renal development, injury, and repair. HGF also serves a protective role in chronic renal disease by preventing tissue fibrosis. Endothelin-1 (ET-1), produced primarily by endothelial cells, is a potent vasoconstrictor that also acts as a proinflammatory peptide, promoting vascular injury and renal damage. In addition to mediating a variety of epithelial cell responses, HGF also induces hemodynamic changes that are poorly understood. The aim of the present study was to study the acute and chronic effects of HGF on ET-1 production in the kidney. We hypothesized that hemodynamic changes upon HGF treatment are likely mediated by immediate ET-1 release, whereas protection from renal fibrosis in rats chronically treated with HGF is likely due to suppression of ET-1 production. Acute HGF infusion into rats caused a decline in blood pressure that was enhanced by pretreatment with bosentan (an endothelin A and B receptor antagonist). HGF infusion also resulted in a decline in glomerular filtration rate (GFR) that could be entirely prevented by bosentan, suggesting that HGF acutely increases production and/or release of ET-1, which then mediates the observed decline in GFR. In cultured glomerular endothelial cells, HGF induced ET-1 production in a dose-dependent manner. Moreover, although there was an initial increase in ET-1 production upon HGF treatment, longer administration suppressed ET-1 production. This finding was consistent with the observation in vivo of a decrease in ET-1 production in renal parenchyma of rats chronically treated with HGF. Our data suggest both a hemodynamic and biological role for HGF-mediated ET-1 regulation.
authors.affiliation: Diivsion of Renal Diseases, Brown University School of Medicine, Rhode Island Hospital, 593 Eddy St., Providence, RI 02903, USA.
authors.forename: Purba
authors.initials: P
authors.lastname: Biswas
authors.forename: Abinash
authors.initials: A
authors.lastname: Roy
authors.forename: Rujun
authors.initials: R
authors.lastname: Gong
authors.forename: Angelito
authors.initials: A
authors.lastname: Yango
authors.forename: Evelyn
authors.initials: E
authors.lastname: Tolbert
authors.forename: Jason
authors.initials: J
authors.lastname: Centracchio
authors.forename: Lance D
authors.initials: LD
authors.lastname: Dworkin
mesh_terms: D000804:Angiotensin II / Q000502:physiology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D000077300:Bosentan; D002417:Cattle; D002478:Cells, Cultured; D004334:Drug Administration Schedule; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D005919:Glomerular Filtration Rate / Q000187:drug effects* / Q000502:physiology; D017228:Hepatocyte Growth Factor / Q000097:blood / Q000494:pharmacology* / Q000652:urine; D007668:Kidney / Q000378:metabolism; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D019332:Endothelin-1; D013449:Sulfonamides; D013777:Tetrazoles; D000804:Angiotensin II; D017228:Hepatocyte Growth Factor; D000077300:Bosentan; C081643:candesartan