Selective Na+/H+ exchange inhibition by cariporide reduces liver fibrosis in the rat.
The aim of this study was to evaluate the effect of cariporide, a selective Na(+)/H(+) exchange inhibitor, on isolated and cultured hepatic stellate cells (HSCs) and in 2 in vivo models of rat liver fibrosis. Platelet-derived growth factor (PDGF)-induced HSC proliferation, evaluated by measuring the percentage of bromodeoxyuridine-positive cells, was significantly inhibited by cariporide, with a maximal effect at 10 micromol/L. Incubation with cariporide did not inhibit PDGF-induced extracellular-regulated kinase 1/2 (ERK1/2), Akt (a downstream component of the phosphatidylinositol [PI]-3 kinase pathway), and protein kinase C (PKC) activation but reduced PDGF-induced activation of the Na(+)/H(+) exchanger, with a maximal effect at 10 micromol/L. Rats treated with dimethylnitrosamine (DMN; 10 mg/kg) for 1 and 5 weeks received a diet with or without 6 ppm cariporide. Treatment with cariporide reduced the degree of liver injury, as determined by alanine aminotransferase (ALT) values, also when administered after the induction of hepatic damage. This was associated with reduced HSC activation and proliferation and reduced collagen deposition, as determined by morphometric evaluation of alpha-smooth muscle actin (SMA)/proliferating cell nuclear antigen-positive cells and percentage of Sirius red-positive parenchyma, respectively. Moreover, cariporide was also able to reduce alpha(1)I procollagen messenger RNA (mRNA) expression. Similar effects were observed in bile duct-ligated (BDL) rats. In conclusion, selective inhibition of the Na(+)/H(+) exchanger by cariporide may represent an effective therapeutic strategy in the treatment of hepatic fibrosis.
Di Sario
Antonio
A
Department of Gastroenterology, University of Ancona, Italy. a.disario@mta01@unian.it
Bendia
Emanuele
E
Taffetani
Silvia
S
Marzioni
Marco
M
Candelaresi
Cinzia
C
Pigini
Paola
P
Schindler
Ursula
U
Kleemann
Heinz-Werner
HW
Trozzi
Luciano
L
Macarri
Giampiero
G
Benedetti
Antonio
A
D000818:Animals; D001652:Bile Ducts; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004128:Dimethylnitrosamine / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology*; D008026:Ligation; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology*
D006146:Guanidines; D010982:Platelet-Derived Growth Factor; D011518:Proto-Oncogene Proteins; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C093373:cariporide; D020797:Receptor, Platelet-Derived Growth Factor beta; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D004128:Dimethylnitrosamine