Abstract
Alcohol usage is linked to increased blood pressure and fibrotic transformation of the liver. Angiotensinogen (AGT) is the source of Ang II which regulates blood pressure and participates in fibrotic transformation of the liver after the hepatocyte death. Ang II is produced from AGT by sequential action of renin followed by angiotensin converting enzyme. The levels of AGT are less than the MichaelisMenten constant of renin. Therefore, an increase in blood AGT levels would result into corresponding increase in Ang II levels that might affect blood pressure regulation and liver fibrogenic processes.
Alcohol metabolism by the liver produces oxidative stress (ROS) that activates hypoxia inducible transcription factor-1alpha (HIF-1α). Moreover, alcohol-mediated hepatic injury activate immune responses causing increased interleukin-1β and other cytokines levels which further increase cellular ROS levels. Since hepatocytes lose alcohol metabolizing enzymes after passages, the alcohol mediated HIF-1&aplha; activation was studied by treatment of hepatocytes with hypoxia mimetics to investigate the effects on AGT secretion. It was observed that angiotensinogen levels were increased with HepG2 and Huh7 after deferoxamine (60nM and 120 nM) and cobalt chloride (10mM and 20mM) post four hours and six hours treatment. . The presence of hypoxia response element(s) (HRE) in human angiotensinogen 5.0 kb promoter was analyzed by ApoE program. The consensus HRE sequences were searched and a total of 5 HREs were found. It is likely that hypoxia mimetics increase angiotensinogen secretion through HREs and these HREs may cause increased AGT secretion from hepatocytes after ethanol exposure.
Faculty Sponsors
Aarti Raja, Ph.D., Rais Ansari, Ph.D.
Project Type
Event
Location
Alvin Sherman Library
Start Date
4-10-2015 1:00 PM
End Date
4-10-2015 5:30 PM
Hypoxia Inducible Factor Mediated Human Angiotensinogen Gene Regulation
Alvin Sherman Library
Alcohol usage is linked to increased blood pressure and fibrotic transformation of the liver. Angiotensinogen (AGT) is the source of Ang II which regulates blood pressure and participates in fibrotic transformation of the liver after the hepatocyte death. Ang II is produced from AGT by sequential action of renin followed by angiotensin converting enzyme. The levels of AGT are less than the MichaelisMenten constant of renin. Therefore, an increase in blood AGT levels would result into corresponding increase in Ang II levels that might affect blood pressure regulation and liver fibrogenic processes.
Alcohol metabolism by the liver produces oxidative stress (ROS) that activates hypoxia inducible transcription factor-1alpha (HIF-1α). Moreover, alcohol-mediated hepatic injury activate immune responses causing increased interleukin-1β and other cytokines levels which further increase cellular ROS levels. Since hepatocytes lose alcohol metabolizing enzymes after passages, the alcohol mediated HIF-1&aplha; activation was studied by treatment of hepatocytes with hypoxia mimetics to investigate the effects on AGT secretion. It was observed that angiotensinogen levels were increased with HepG2 and Huh7 after deferoxamine (60nM and 120 nM) and cobalt chloride (10mM and 20mM) post four hours and six hours treatment. . The presence of hypoxia response element(s) (HRE) in human angiotensinogen 5.0 kb promoter was analyzed by ApoE program. The consensus HRE sequences were searched and a total of 5 HREs were found. It is likely that hypoxia mimetics increase angiotensinogen secretion through HREs and these HREs may cause increased AGT secretion from hepatocytes after ethanol exposure.
