AT1 receptor downregulation: A mechanism for improving glucose homeostasis

Abstract

There is a pathophysiological correlation between arterial hypertension and diabetes mellitus, established since the pre-diabetic state in the entity known as insulin resistance. It is known that high concentrations of angiotensin-II enable chronic activation of the AT1 receptor, promoting sustained vasoconstriction and the consequent development of high blood pressure. Furthermore, the chronic activation of the AT1 receptor has been associated with the development of insulin resistance. From a molecular outlook, the AT1 receptor signaling pathway can activate the JNK kinase. Once activated, this kinase can block the insulin signaling pathway, favoring the resistance to this hormone. In accordance with the previously mentioned mechanisms, the negative regulation of the AT1 receptor could have beneficial effects in treating metabolic syndrome and type 2 diabetes mellitus. This review explains the clinical correlation of the metabolic response that diabetic patients present when receiving negatively regulatory drugs of the AT1 receptor.

The Renin–Angiotensin System (RAS) in COVID-19 Disease: Where We Are 3 Years after the Beginning of the Pandemic

“…The first is produced by the kidney and hydrolases the pro-hormone angiotensinogen, released by the liver, into angiotensin I (AngI) [ 3 ], while the second enzyme catalyzes the cleavage of AngII from AngI [ 3 ] ( Figure 1 ). Depending on the target organ, AngII binding to its transmembrane AT1 receptor induces vasoconstriction (in vascular smooth muscles), sodium reabsorption (in the kidney), or aldosterone production (in the adrenal cortex) [ 3 , 4 ]. Indeed, AngII is a strong vasoconstrictor and pro-inflammatory hormone that acts both at renal and vascular levels to enhance the peripheral resistance of vessels, ultimately leading to high blood pressure (HBP) [ 5 ].…”

MicroRNA-155 mediates endogenous angiotensin II type 1 receptor regulation: implications for innovative type 2 diabetes mellitus management

“…The pathophysiological role of the renin angiotensin aldosterone system (RAAS) and its major effector, Angiotensin II (Ang II) through the Ang II Type 1 receptor (AT1R), in the development of IR in T2DM have long been recognized[ 6 ]. Furthermore, convincing evidence exists advocating the use of RAAS inhibition, ACE inhibitors (ACEi) or AT1 receptor antagonists/blockers (ARB), in patients with T2DM, not only for proteinuria and HT, but also as a means to improve IR and glucose homeostasis[ 6 ].…”

“…MiR-155 is of particular interest as it is intricately involved both in the pathogenesis of DM and the regulation of AT1R and Ang II effects (Figure 1 )[ 6 , 8 - 12 ]. First identified in 1997, miR-155 is a highly conserved and ancient miRNA primarily expressed in the thymus and spleen.…”

“…In addition, RAAS’s protective arm, involving Ang 1-7/AT2R/MasR signaling, is inhibited at the same time, further augmenting an unfavorable AT1R/AT2R imbalance[ 26 , 27 ]. MiR-155, acting as a master regulator, is the key player in chronic RAAS/Ang II/AT1R activation, thereby, intricately associated with the development of IR[ 6 ]. Through its repression of the AGTR1 (the gene that codes for the AT1R) miR-155 regulates the homeostasis of the AT1R receptor, its membrane presence, and thus the biological activity of Ang II (Table 1 )[ 9 , 10 , 28 - 30 ].…”

“…AT1R substrate modulation (ACEi) and/or receptor inhibition (ARBs) may improve glucose homeostasis[ 6 ]. However, strategies to increase an ailing miR-155 production in T2DM could prove to be a more appropriate course of action (Figure 1 ).…”