Hepatocyte growth factor may function as a renotropic factor for regeneration in rats with acute renal injury

Hepatocyte growth factor (HGF), a potent mitogen for mature hepatocytes, possesses mitogenic and morphogenic activities for renal epithelial cells. To examine the renotropic function of HGF, we investigated the expression of HGF mRNA and HGF activity in the rat kidney after acute renal failure. When acute renal failure was induced by ischemia or by HgCl2 administration, a DNA synthesis occurred predominantly in the renal tubular cells located in the outer medulla with a peak at 48 h after the treatments. In both renal injuries, HGF mRNA in the kidney increased markedly, reaching a maximum 6 to 12 h after the treatments. HGF activity in the kidney also increased to three- to fourfold higher level than the normal level at 12 h after ischemic treatment or HgCl2 administration. In situ hybridization and immunohistochemical analysis indicated that both HGF mRNA and HGF protein were expressed in renal interstitial cells, presumably endothelial cells and macrophages, but not in tubular epithelial cells. In addition, HGF activity in the plasma of rats with renal ischemia or HgCl2 administration rapidly increased, reaching a maximum at 6 h after the treatment. One week after these injuries, HGF mRNA and HGF activity reverted to normal levels, and renal tubular cell regeneration ceased. Moreover, intravenous injection of human recombinant HGF into mice with acute renal failure caused by HgCl2 administration stimulated DNA synthesis of renal tubular cells in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Download Full-text

Single Injection of Naked Plasmid Encoding Hepatocyte Growth Factor Prevents Cell Death and Ameliorates Acute Renal Failure in Mice

Journal of the American Society of Nephrology ◽

10.1681/asn.v132411 ◽

2002 ◽

Vol 13 (2) ◽

pp. 411-422 ◽

Cited By ~ 1

Author(s):

Chunsun Dai ◽

Junwei Yang ◽

Youhua Liu

Keyword(s):

Renal Failure ◽

Cell Death ◽

Acute Renal Failure ◽

Folic Acid ◽

Growth Factor ◽

Epithelial Cells ◽

Hepatocyte Growth Factor ◽

Intravenous Injection ◽

Naked Plasmid ◽

Hepatocyte Growth

ABSTRACT. Hepatocyte growth factor (HGF) is a pleiotrophic factor that plays an important role in tissue repair and regeneration after injury. The expression of both HGF and its c-met receptor genes is rapidly upregulated after acute renal injury induced by folic acid. In this study, the role of exogenous HGF in preventing acute renal failure by systemic administration of naked plasmid containing human HGF cDNA driven under the cytomegalovirus promoter (pCMV-HGF) was examined in mice. Intravenous injection of pCMV-HGF plasmid produced substantial levels of human HGF protein in mouse kidneys. Simultaneous injection of HGF plasmid DNA significantly ameliorated renal dysfunctions and accelerated recovery from the acute injury induced by folic acid. Of interest, preadministration of HGF plasmid 24 h before folic acid injection dramatically protected renal epithelial cells from both apoptotic and necrotic death and preserved the structural and functional integrity of renal tubules. Expression of HGF transgene activated protein kinase B/Akt kinase and preserved prosurvival Bcl-xL protein expression in vivo. These results indicate that a single, intravenous injection of naked plasmid containing HGF gene not only promotes renal regeneration after injury but also protects tubular epithelial cells from the initial injury and cell death in the first place. These data suggest that HGF gene therapy may provide a new avenue for exploring a novel therapeutic strategy for clinical acute renal failure.

Download Full-text

Hepatocyte growth factor is a paracrine factor for renal epithelial cells: Stimulation of DNA synthesis and Na,K-ATPase activity

Biochemical and Biophysical Research Communications ◽

10.1016/0006-291x(92)91825-b ◽

1992 ◽

Vol 182 (2) ◽

pp. 960-965 ◽

Cited By ~ 34

Author(s):

Kenichi Ishibashi ◽

Sei Sasaki ◽

Hisato Sakamoto ◽

Yoshiko Nakamura ◽

Toshihiko Hata ◽

...

Keyword(s):

Growth Factor ◽

Epithelial Cells ◽

Hepatocyte Growth Factor ◽

Atpase Activity ◽

Dna Synthesis ◽

Paracrine Factor ◽

Renal Epithelial Cells ◽

Hepatocyte Growth ◽

Stimulation Of

Download Full-text

Recovery from Acute Ischaemic Renal Failure is Accelerated by Des-(1–3)-Insulin-Like Growth Factor-1

Clinical Science ◽

10.1042/cs0860709 ◽

1994 ◽

Vol 86 (6) ◽

pp. 709-714 ◽

Cited By ~ 21

Author(s):

Ross Clark ◽

Deborah Mortensen ◽

Ralph Rabkin

Keyword(s):

Renal Failure ◽

Acute Renal Failure ◽

Growth Factor ◽

Fractional Excretion ◽

Insulin Like Growth Factor ◽

Ischaemic Injury ◽

Beneficial Effects ◽

Nitrogen Levels ◽

Renal Tubular Cells ◽

Renal Tubular

1. Acute renal failure carries a high risk of morbidity and mortality, so there is a need for agents that minimize renal injury after an insult and that hasten repair. Insulin-like growth factor-1 is mitogenic for renal tubular cells; in normal kidneys it has haemodynamic effects and it is potently anabolic. We tested the theory that insulin-like growth factor-1 may be of use in the treatment of acute renal failure by administering recombinant des-(1–3)-insulin-like growth factor-1, a truncated form of insulin-like growth factor-1, which occurs naturally. Ischaemic renal failure was induced in normal rats by occluding both renal pedicles for 60 min. Then des-(1–3)-insulin-like growth factor-1 (0.8 mg day−1 kg−1) or vehicle was given by subcutaneous minipump for 7 days. The rats were weighed and bled daily and in one experiment were housed in metabolic cages and urine was collected. 2. Des-(1–3)-insulin-like growth factor-1 caused a lower and earlier peak in both serum creatinine and blood urea-nitrogen levels, and a more rapid and complete return toward basal values than in untreated animals. Also des-(1–3)-insulin-like growth factor-1 significantly increased creatinine clearance and reduced fractional excretion of filtered sodium. Besides these beneficial effects on kidney function, des-(1–3)-insulin-like growth factor-1 was anabolic as treated rats gained weight while control rats lost weight. The mortality in control rats was 28% compared with 6% in treated rats. 3. Thus des-(1–3)-insulin-like growth factor-1 accelerated recovery from acute ischaemic injury and may be useful for the treatment of acute renal failure.

Download Full-text