Hormones – Cytokines – Signaling
Kidney International (2001) 59, 1304–1314; doi:10.1046/j.1523-1755.2001.0590041304.x
Hepatocyte growth factor suppresses interstitial fibrosis in a mouse model of obstructive nephropathy
Shinya Mizuno, Kunio Matsumoto and Toshikazu Nakamura
Division of Biochemistry, Department of Oncology, Biomedical Research Center, Osaka University Graduate School of Medicine, Yamadaoka, Japan
Correspondence: Toshikazu Nakamura, Ph.D., Division of Biochemistry, Department of Oncology, Biomedical Research Center, Osaka University Graduate School of Medicine, Yamadaoka 2-2-B7, Suita 565-0871, Japan. E-mail: nakamura@onbich.med.osaka-u.ac.jp
Received 3 May 2000; Revised 25 September 2000; Accepted 30 October 2000.
Abstract
Hepatocyte growth factor suppresses interstitial fibrosis in a mouse model of obstructive nephropathy.
Background
As tubulointerstitial fibrosis (TIF) reflects the prognosis of patients with various chronic renal diseases, the pathogenesis of TIF has to be clarified. Transforming growth factor-
(TGF-) is a key mediator for renal fibrosis. We reported that hepatocyte growth factor (HGF) prevents renal fibrosis in nephrotic mice. However, the function of HGF in chronic renal failure, except for nephrotic syndrome, remains to be determined.
Methods
Using mice subjected to unilateral ureter-ligated obstruction (UUO), we investigated the roles of HGF in TIF, as induced by obstructive nephropathy. Pathophysiological changes in the kidney after UUO treatment were analyzed focusing on expressions of renal HGF and TGF-, TIF, tubular proliferation, and apoptosis. Neutralizing antibody against rodent HGF, or recombinant human HGF (rhHGF), was administrated to the UUO mice, and pathophysiological changes after neutralization or supplements of HGF were analyzed.
Results
In this UUO model, TIF with tubular apoptosis became evident, and it was accompanied by a decrease in renal HGF expression and an increase in renal TGF- expression. Neutralization of endogenous HGF accelerated the progression of TIF, accompanied by increases in TGF- expression and tubular apoptosis as well as by decreases in tubular proliferation. In contrast, rhHGF attenuated TIF progression, and there were decreases in TGF- expression and tubular apoptosis, and an increase in tubular proliferation.
Conclusions
Endogenous as well as exogenous HGF attenuated the progression of the fibrosis caused by obstructive nephropathy in these mice. Thus, local reduction in HGF levels may account for TIF in chronic renal diseases.
Keywords:
chronic renal disease, macrophages, renal fibrosis, transforming growth factor-, tubulointerstitial fibrosis
