Hepatocyte growth factor: A regulator of extracellular matrix genes in mouse mesangial cells

The potential rule of hepatocyte growth factor (HGF) in regulating extracel lular matrix in mouse mesangial cells (MMC) was evaluated. Functional HGF r eceptors were detected in MMC by HGF-induced extracellular acidification, a response that was inhibited by the HGF inhibitor HGF/NK2, a splice variant expressing the N-terminal domain through the second kringle domain. HGF al so increased fibronectin and collagen alpha 1 (IV) mRNA levels in these cel ls; the increases were associated with a concentration dependent increase i n transcriptional activity of the collagen oil (IV) gene. HGF also stimulat ed fibronectin and collagen alpha 1 (IV) mRNA levels in primary rabbit prox imal tubule epithelial cells. To evaluate the potential consequences of chr onic elevation of HGF on renal function, HGF was administered continuously for 18 days to normal and diabetic C57BLKS/J lepr(db) mice. In the diabetic mice, HGF reduced creatinine clearance and increased microalbuminuria, ind icating that chronic exposure to HGF impairs renal function. Thus, chronica lly elevated HGF:may contribute to the progression of chronic renal disease in diabetes by decreasing the glomerular filtration rate and possibly prom oting the accumulation of extracellular matrix. BIOCHEM PHARMACOL 59;7:847- 853, 2000. (C) 2000 Elsevier Science Inc.