Hepatocyte Growth Factor Gene Therapy and Angiotensin II Blockade Synergistically Attenuate Renal Interstitial Fibrosis in Mice

Abstract

ABSTRACT. Tubulointerstitial fibrosis is considered to be common endpoint result of many forms of chronic renal diseases. Except for renal replacement, chronic renal fibrosis is presently incurable. This study demonstrates that the combination of hepatocyte growth factor (HGF) gene therapy with inhibition of the renin-angiotensin system produced synergistic beneficial effects leading to dramatic attenuation of renal tubulointerstitial fibrosis in obstructive nephropathy in mice. The combined treatment with human HGF gene and losartan, an angiotensin II (AngII) type I receptor blocker, preserved renal mass and gross morphology of the obstructed kidneys. Although HGF gene therapy alone inhibited the expression of α-smooth muscle actin (αSMA) by approximately 54% and 60% at day 7 and day 14 after surgery, respectively, its combination with losartan almost completely abolished αSMA induction in the obstructed kidneys. The combined therapy also synergistically inhibited the accumulation of interstitial matrix components, such as fibronectin and collagen I, and suppressed renal expression of transforming growth factor-β1 (TGF-β1) and its type I receptor. In vitro studies revealed that AngII by itself did not induce αSMA, but it drastically potentiated TGF-β1-initiated αSMA expression in tubular epithelial cells. Furthermore, HGF abrogated de novo αSMA expression induced by TGF-β1 plus AngII. These results suggest that many factors are implicated in the pathogenesis of renal interstitial fibrosis; therefore, a combined therapy aimed at simultaneously targeting multiple pathologic pathways may be necessary for halting the progression of chronic renal diseases. These findings may provide the basis for designing future therapeutic regimens for blocking progressive renal fibrosis in patients. E-mail: liuy@msx.upmc.edu

Plasminogen-Mediated Activation and Release of Hepatocyte Growth Factor from Extracellular Matrix

“…Elevation of HGF levels by its exogenous delivery (22,23) or by gene transfer (24) reduces the amount of fibrosis that occurs after lung injury. This antifibrotic effect is not unique to the lung, but occurs in other organs, including liver (51), kidney (52,53), skin (54), and heart (55).…”

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…Treatment with HGF suppressed, and blockade of HGF worsened, experimental renal fibrosis (287)(288)(289). Importantly, HGF administration synergized with angiotensin-II blockade in antagonizing renal fibrosis (290). In experimental kidney transplant models, treatment with human recombinant HGF or human HGF gene therapy (immediately before or after transplantation) prevented kidney allograft inflammation and fibrosis (291,292).…”

Intravenous Administration of Hepatocyte Growth Factor Gene Ameliorates Diabetic Nephropathy in Mice

“…Two sets of animal experiments were carried out. For studying the effects of HGF on normal kidney, groups of mice were administered the human HGF expression plasmid (pCMV-HGF) or empty vector (pcDNA3) by intravenous injection, as described previously (17,23). Mice received weekly injections of plasmid DNA at a concentration of 1 mg/kg body wt for 8 wk.…”

“…In vitro, HGF specifically antagonizes the profibrotic actions of TGF-␤1 and blocks myofibroblast activation from interstitial fibroblasts and mesenchymal transition from tubular epithelial cells (10,15). In vivo, HGF inhibits renal TGF-␤1 expression and mitigates fibrotic lesions after various chronic injuries (10,12,16,17). Recent studies indicate that the antifibrotic actions of HGF are primarily mediated by specifically interrupting TGF-␤1/Smad signal transduction (15,18,19).…”