Role of Deranged Energy Deprivation Signaling in the Pathogenesis of Cardiac and Renal Disease in States of Perceived Nutrient Overabundance.

Role of Deranged Energy Deprivation Signaling in the Pathogenesis of Cardiac and Renal Disease in States of Perceived Nutrient Overabundance. Circulation. 2020 Mar 13;: Authors: Packer M Abstract Sodium-glucose cotransporter 2 inhibitors reduce the risk of serious heart failure and adverse renal events, but the mechanisms that underlie this benefit are not understood. Treatment with SGLT2 inhibitors is distinguished by two intriguing features - ketogenesis and erythrocytosis. Both reflect the induction of a fasting-like and hypoxia-like transcriptional paradigm that is capable of restoring and maintaining cellular homeostasis and survival. In the face of perceived nutrient and oxygen deprivation, cells activate low-energy sensors, which include sirtuin-1 (SIRT1), adenosine monophosphate-activated protein kinase (AMPK) and hypoxia inducible factors (especially HIF-2α); these enzymes and transcription factors are master regulators of hundreds of genes and proteins that maintain cellular homeostasis. The activation of SIRT1 (through its effects to promote gluconeo-genesis and fatty acid oxidation) drives ketogenesis, and working in concert with AMPK, it can directly inhibit inflammasome activation and maintain mitochondrial capacity and stability. Hypoxia inducible factors act to promote oxygen delivery (by stimulating erythropoietin and erythrocytosis) and decrease oxygen consumption. Most importantly, the activation of SIRT1, AMPK an...
Source: Circulation - Category: Cardiology Authors: Tags: Circulation Source Type: research