mTOR Dysregulation, Insulin Resistance, and Hypertension

Abstract

Worldwide, diabetes mellitus (DM) and cardiovascular diseases (CVDs) represent serious health problems associated with unhealthy diet and sedentarism. Metabolic syndrome (MetS) is characterized by obesity, dyslipidemia, hyperglycemia, insulin resistance (IR) and hypertension. The mammalian target of rapamycin (mTOR) is a serine/threonine kinase with key roles in glucose and lipid metabolism, cell growth, survival and proliferation. mTOR hyperactivation disturbs glucose metabolism, leading to hyperglycemia and further to IR, with a higher incidence in the Western population. Metformin is one of the most used hypoglycemic drugs, with anti-inflammatory, antioxidant and antitumoral properties, having also the capacity to inhibit mTOR. mTOR inhibitors such as rapamycin and its analogs everolimus and temsirolimus block mTOR activity, decrease the levels of glucose and triglycerides, and reduce body weight. The link between mTOR dysregulation, IR, hypertension and mTOR inhibitors has not been fully described. Therefore, the main aim of this narrative review is to present the mechanism by which nutrients, proinflammatory cytokines, increased salt intake and renin-angiotensin-aldosterone system (RAAS) dysregulation induce mTOR overactivation, associated further with IR and hypertension development, and also mTOR inhibitors with higher potential to block the activity of this protein kinase.

Keywords: inhibitors; insulin resistance; mTOR dysregulation; metformin; obesity; protein kinases; sedentarism.

Figure 1

Phosphatidylinositol 3-kinase (PI3K) protein kinases B (AKT)/mammalian target of rapamycin (mTOR) pathway in healthy conditions: Nutrients, growth factors, cytokines and insulin bind to tyrosine kinases receptors (RTKs), leading to insulin receptors substrate 1 or 2 (IRS1/IRS2) activation and further AKT activation by phosphorylation. Once activated, AKT will phosphorylate other protein kinases such as mTOR, composed of the two complexes mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTORC1 activates sterol response element binding protein (SREBP) and eukaryotic translation initiator factor 4E binding protein (4EBP) and 70Ka ribosomal protein S56 kinase 1 (p70S6K1), leading to lipid and protein synthesis, respectively. mTORC1 inhibits the activity of unc-51-like kinase 1 (ULK1) and autophagy-related gene 13 (ATG13) blocking autophagy. Inactivation of AKT substrate 160 (AS160) and glycogen synthase 3 (GSK3) induces plasma membrane GLUT translocation. mTORC2 activates other protein kinases such as A, G and C, which positively regulate cellular metabolism. Activation of PI3K/AKT/mTOR will be correlated with cell growth, survival and proliferation. “+” activation.

Figure 2

Phosphatidylinositol 3-kinase (PI3K) protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway, insulin resistance and hypertension. Hypercaloric diet, branched-chain amino acids (BCAAs), proinflammatory cytokines, free fatty acids (FFAs), increased salt intake, the renin–angiotensin–aldosterone system (RAAS) and salt-inducible kinase (SIK) induce mTOR hyperactivation via RTKs or insulin receptor substrates (IRS1/2). IRS phosphorylation produced by angiotensin II (Ang II) and aldosterone decreases nitric oxide (NO) synthesis. Activation of 70Ka ribosomal protein S6 kinase 1 (p70S6K1) and glycogen synthase 3 (GSK3) inhibits IRS conducing to an increased blood glucose level because GLUT will be blocked inside the cell. mTOR complex 2 (mTORC2) activates serum/glucocorticoid-regulated kinase 1 (SGK1) stimulating Na transport. mTOR over-activation is associated with synthesis of advanced end products (AGEs), reactive oxygen species (ROS), reactive nitrogen species (RNS) and lipids. Metformin has the capacity to inhibit mTOR, while rapamycin, everolimus, temsirolimus and sodium-glucose transporter protein 2 (SGLT2) block mTORC1. All these events will lead to insulin resistance (IR) and further to hypertension. “+” activation; “↓” decrease; “↑” increase.

Figure 3

Hyperglycemia is correlated with the activation of the polyol pathway, where glucose is reduced to sorbitol by aldolase reductase (AR) and NADPH. Further, sorbitol will be oxidized to fructose by the enzyme sorbitol dehydrogenase (SDH), and NADH is generated. Fructose will be metabolized into ketone bodies, triose phosphate or carbonylic compounds such as glyoxal, methylglyoxal and 3-deoxyglucose. The last three compounds will contribute to irreversible advanced glycation end product (AGE) formation. NADPH and NADH represent sources for reactive species generation. In hyperglycemic conditions, the hexosamine biosynthesis pathway (HBP) is also activated, leading to the formation of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), which can induce protein damage. Protein kinase C (PKC) is activated by hyperglycemia, which has the capacity to activate polyol and HBP pathways. PKC activation is associated with decreased levels of nitric oxide (NO) biosynthesis and elevated levels of vascular endothelial growth factor (VEGF). All these molecular events will induce, in the end, mTOR dysregulation. “+” activation; “↑” increase; “↓” decrease.