Cholestasis is a clinical syndrome common to a large number of hepatopathies, in which either bile production or its transit through the biliary tract is impaired due to functional or obstructive causes, respectively; the consequent intracellular retention of toxic biliary constituents generates parenchyma damage, largely via oxidative stressmediated mechanisms. Hepatocyte growth factor (HGF) and its receptor c-Met represent the first defense line against hepatotoxic factors, by inducing Nrf2 activation which, in turn, leads to an antioxidant and repair response. In this study, we evaluated the capability of HGF to counteract the damage caused by the model cholestatic agent, α-naphthyl isothiocyanate (ANIT). HGF had clear anti-cholestatic effects, as apparent from the improvement in both bile flow and liver function test. Histology examination revealed a significant reduction of injured areas. HGF also preserved hepatocellular tight-junctional structures. These anticholestatic effects were associated with the induction of basolateral efflux ABC transporters, which facilitates extrusion of toxic biliary compounds and its further alternative depuration via urine. The biliary epithelium seems to have been also preserved, as suggested by a normalization in serum GGT levels, CFTR expression, and cholangyocyte primary cilium structure. Finally, we are reporting that HGF also protects the kidneys and their function from the impairment provoked by ANIT-induced cholestasis (cholemic nephropathy). In conclusion, the results clearly show for the first time that HGF protects the liver and kidneys from a cholestatic injury.

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