Differential impacts of mineralocorticoid receptor antagonist potassium canrenoate on liver and renal changes in high fat diet-mediated early hepatocarcinogenesis model rats

• Published in: Journal of toxicological sciences 2018, Vol.43(10), pp.611-621
• Main Authors: Nakamura, Misato, Eguchi, Ayumi, Inohana, Mari, Nagahara, Rei, Murayama, Hirotada, Kawashima, Masashi, Mizukami, Sayaka, Koyanagi, Mihoko, Hayashi, Shim-mo, Maronpot, Robert R., Shibutani, Makoto, Yoshida, Toshinori
• Format: Article
• Language: English
• Subjects: alpha-Glycosyl isoquercitrin; Animals; Antioxidants; Antioxidants - administration & dosage; Antioxidants - pharmacology; Blood glucose; Canrenoic Acid - administration & dosage; Canrenoic Acid - pharmacology; Catalase; Catalase - metabolism; Diet; Diet, High-Fat - adverse effects; Disease Models, Animal; Fatty liver; Gene Expression; Glucose tolerance; Glutathione; Glutathione S-Transferase pi - metabolism; Glutathione transferase; High fat diet; Insulin; Kidney - metabolism; Kidney - pathology; Lesions; Liver; Liver - metabolism; Liver - pathology; Liver diseases; Liver Neoplasms - etiology; Liver Neoplasms - pathology; Mineralocorticoid Receptor Antagonists - administration & dosage; Mineralocorticoid Receptor Antagonists - pharmacology; NAD(P)H oxidase; NADPH oxidase; NADPH Oxidases - genetics; NADPH Oxidases - metabolism; NADPH Oxidases - physiology; NOX4 protein; Obesity; Organ Specificity; Placenta; Potassium; Potassium canrenoate; Preneoplastic liver lesions; Quercetin - administration & dosage; Quercetin - analogs & derivatives; Quercetin - pharmacology; Receptors, Mineralocorticoid - metabolism; Receptors, Mineralocorticoid - physiology; Rodents; Signal Transduction - drug effects; Signal Transduction - physiology; Signaling; Steatosis; Tubules; Two-stage hepatocarcinogenesis model
• ISSN: 0388-1350; 1880-3989
• DOI: 10.2131/jts.43.611

Mineralocorticoid receptor (MR)/NADPH oxidase (NOX) signaling is involved in the development of obesity, insulin resistance, and renal diseases; however, the role of this signaling on steatotic preneoplastic liver lesions is not fully elucidated. We determined the effects of the MR antagonist potassium canrenoate (PC) on MR/NOX signaling in hepatic steatosis and preneoplastic glutathione S-transferase placental form (GST-P)-positive liver foci. Rats were subjected to a two-stage hepatocarcinogenesis model and fed with basal diet or high fat diet (HFD) that was co-administered with PC alone or in combination with the antioxidant alpha-glycosyl isoquercitrin (AGIQ). PC reduced obesity and renal changes (basophilic tubules that expressed MR and p22phox) but did not affect blood glucose tolerance and non-alcoholic fatty liver disease activity score (NAS) in HFD-fed rats. However, the drug increased the area of GST-P-positive liver foci that expressed MR and p22phox as well as increased expression of NOX genes (p22phox, Poldip2, and NOX4). PC in combination with AGIQ had the potential of inhibiting the effects of PC on the area of GST-P-positive liver foci and the effects were associated with increasing expression of an anti-oxidative enzyme (Catalase). The results suggested that MR/NOX signaling might be involved in development of preneoplastic liver foci and renal basophilic changes in HFD-fed rats; however, the impacts of PC were different in each organ.