Production and activation of hepatocyte growth factor in acute renal failure

Hepatocyte growth factor (HGF) facilitates the regeneration of injured kidney in acute renal failure (ARF). HGF is produced as a single-chain precursor by cells of mesenchymal origin and is converted to a biologically active, heterodimeric molecule by proteolytic processing. We studied HGF mRNA and protein levels in systemic organs of glycerol-induced ARF rats, a model of crush syndrome. HGF protein concentration of tissue homogenate was measured by ELISA. Both mRNA and protein levels were increased in liver and spleen at 24 hours after the glycerol injection whereas HGF protein level was decreased in the injured kidney. Expression of HGF receptor/c-met mRNA was elevated only in the kidney. These results suggest that HGF supplied in an endocrine manner may play an important role in the regenerating process following ARF. Next, we measured serum HGF concentration by ELISA in 8 ARF patients caused by crush syndrome and the molecular size of serum HGF was determined by immunoblotting. Although serum HGF levels elevated in all patients, the HGF levels did not associate with their prognoses. While a single-chain molecule was predominantly observed in sera from chronic renal failure patients and healthy subjects, the majority of serum HGF was a heterodimeric form in 7 ARF patients. In one patient who developed disseminated intravascular coagulation syndrome and had a poor prognosis, a single-chain molecule was predominant although the serum HGF concentration was equivalent. These data suggest that the activity of proteolytic processing may be also an important factor for the expression of the biological function of HGF.