Inhibition of the Na+/H+ exchanger reduces rat hepatic stellate cell activity and liver fibrosis: An in vitro and in vivo study

Antifibrogenic effects of canrenone, an antialdosteronic drug, on human hepatic stellate cells

“…34,49 Inhibition of the activity of the NHE by pretreatment with amiloride inhibits PDGF-induced mitogenesis, thus indicating that changes in [pH] i induced by this growth factor are essential for its full biological activity. 33 Along these lines, a role of NHE1, either obligatory or permissive, in the specific cell functions of proliferation, survival, and migration induced by growth factors has recently received the most attention. 48 Our results indicate that, although canrenone is unable to block the activity of the exchanger in response to an acid load, unless used at high dosage (i.e., 50 mol/L), it is able to inhibit the antiporter activity stimulated by PDGF.…”

“…Indeed, as previously stated, PI 3-K activity is known to be necessary for both proliferation and migration induced by PDGF in human HSC, whereas the activity of the NHE has been shown to be relevant only for PDGF-induced cell proliferation. 23,28,33 To address this issue, the action of canrenone on PDGF-induced PI 3-K activity and its biological effects was compared with that of 2 established NHE1 inhibitors, i.e., EIPA and HOE 642. These compounds, which belong to 2 distinct pharmacological classes, are thought to act by competitively inhibiting Na ϩ binding sites at the extracellular cation-binding site of NHE1, with HOE 642 known to be approximately 10 2 -10 3 -fold more specific than EIPA.…”

“…24,25 Previous reports obtained in rat HSC have indicated that preincubation with EIPA is able to reduce collagen type I synthesis in cell supernatants induced by oxidative stress, 58 but not that induced by TGF-␤. 33 However, in these studies, collagen type I synthesis was assessed by enzyme-linked immunosorbent assay as protein accumulation in cell supernatants. Our data indicate that TGF-␤-induced de novo synthesis (evaluated by metabolic labeling and immunoprecipitation) of different ECM componentsnamely, collagen type I, collagen type IV, and fibronectin-is affected by cell preincubation with canrenone.…”

“…30,33,34 We first evaluated the effect of this drug on the basal activity of the Na ϩ /H ϩ exchanger (NHE) that regulates [pH ] i in HSC. As illustrated in Figure 6, untreated cells (control) recovered readily from an acute acid load in a Na ϩ -free medium on reintroduction of Na ϩ .…”

Bioconjugation of Oligonucleotides for Treating Liver Fibrosis

“…Pentoxifylline, a phosphodiesterase inhibitor, decreases HSC proliferation in vitro and in vivo by inhibiting PDGF-related signaling (226)(227)(228). Amiloride, an Na+/H+ exchanger inhibitor, decreases PDGF-induced proliferation and modulates the fibrogenic effect of oxidative stress in HSCs (229,230) and has also been shown to be effective in experimental liver fibrosis (231). Sfarnesylthiosalicylic acid, a ras antagonist, inhibits proliferation and migration of HSCs and reduces thioacetamide-induced liver fibrosis in rats (232).…”