losartan-potassium and Carbon-Tetrachloride-Poisoning

Although the serum-abundant metal-binding protein transferrin (encoded by the Trf gene) is synthesized primarily in the liver, its function in the liver is largely unknown. Here, we generated hepatocyte-specific Trf knockout mice (Trf-LKO), which are viable and fertile but have impaired erythropoiesis and altered iron metabolism. Moreover, feeding Trf-LKO mice a high-iron diet increased their susceptibility to developing ferroptosis-induced liver fibrosis. Importantly, we found that treating Trf-LKO mice with the ferroptosis inhibitor ferrostatin-1 potently rescued liver fibrosis induced by either high dietary iron or carbon tetrachloride (CCl4) injections. In addition, deleting hepatic Slc39a14 expression in Trf-LKO mice significantly reduced hepatic iron accumulation, thereby reducing ferroptosis-mediated liver fibrosis induced by either a high-iron diet or CCl4 injections. Finally, we found that patients with liver cirrhosis have significantly lower levels of serum transferrin and hepatic transferrin, as well as higher levels of hepatic iron and lipid peroxidation, compared with healthy control subjects. Taken together, these data indicate that hepatic transferrin plays a protective role in maintaining liver function, providing a possible therapeutic target for preventing ferroptosis-induced liver fibrosis.

Topics: Animals; Carbon Tetrachloride Poisoning; Cation Transport Proteins; Cyclohexylamines; Cytokines; Erythropoiesis; Erythropoietin; Female; Ferroptosis; Hepatocytes; Homeostasis; Iron; Iron Overload; Iron, Dietary; Lipid Peroxidation; Liver; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle Proteins; Phenylenediamines; Transferrin

Extrarenal sites are the major source of erythropoietin (Ep) production in fetuses and neonates. Afterwards, however, the kidneys are the major site. The most likely site of Ep production is the liver, although attempts to extract Ep from the liver have been, to date, unsuccessful. Extrarenal Ep production, as is the case for renal Ep production, is regulated primarily by the oxygen demand: supply. However, some differences have been identified in the response of extrarenal and renal sites of Ep production to several conditions. Two classes of conditions that selectively influence extrarenal Ep production are the subject of this paper. These are the following: 1) factors that cause reparable hepatic injury--including partial hepatectomy, CC14, and bile duct ligation, and 2) continuous perfusion of angiotensin II. The differences between the mechanism by which these two factors influence extrarenal Ep production will be explored and discussed.

Topics: Angiotensin II; Animals; Captopril; Carbon Tetrachloride Poisoning; Colchicine; Erythropoiesis; Erythropoietin; Female; Indomethacin; Kinetics; Liver; Nephrectomy; Organ Specificity; Rats; Rats, Inbred Strains; Uremia

Liver regeneration after partial hepatectomy is associated with an increase in extrarenal Ep production; however, this surgical procedure is time-consuming and difficult to standardize. Carbon tetrachloride (CCl4) ingestion in rats is an easy and reproducible way to induce liver damage and regeneration. We therefore studied the effects of CCl4 on extrarenal Ep production in rats. Just as is the case following partial hepatectomy, extrarenal Ep production in response to hypoxia was reduced immediately after ingestion of CCl4. Thereafter it rose to supranormal levels which peaked 3 to 4 days after CCl4 ingestion (at this time Ep titers of nephrectomized, CCl4-fed rats rose to greater than 1.0 U/ml of plasma after exposure to 0.42 atmosphere for 7 hr). Extrarenal Ep production then declined, but was still supranormal 7 days after CCl4. Carbon tetrachloride did not significantly affect extrarenal Ep production in rats nephrectomized 18 hr prior to initiation of hypoxia even if they received injections of renin prior to being made hypoxic, nor did it affect Ep production in response to hypoxia in nonnephrectomized rats under the conditions used in this study.

Topics: Animals; Carbon Tetrachloride Poisoning; Erythropoietin; Female; Hypoxia; Kidney; Liver; Liver Regeneration; Nephrectomy; Rats; Renin

Topics: Animals; Biological Assay; Carbon Tetrachloride Poisoning; Constriction; Desoxycorticosterone; Dogs; Erythropoietin; Iron Radioisotopes; Kidney; Liver; Mice; Perfusion; Sheep; Vena Cava, Inferior

Topics: Absorption; Carbon Tetrachloride Poisoning; Chelating Agents; Diet; Dietary Proteins; Epoetin Alfa; Erythropoietin; Intestine, Small; Intestines; Iron; Iron Isotopes; Liver Cirrhosis; Liver Cirrhosis, Experimental; Pharmacology; Polycythemia; Rats; Research; Toxicology