Metabolic reprogramming as the basis for sodium-glucose co-transporter type 2 inhibitors cardio- and nephroprotective effect

Abstract

In recent years, it has been shown that sodium-g lucose co-transporter type 2 inhibitors (SGLT2), drugs for type 2 diabetes mellitus treatment, significantly improve metabolic parameters and have protective effect on the kidneys and heart not only in patients with type 2 diabetes mellitus. New research indicates that the progression of chronic heart failure (CHF) and chronic kidney disease (CKD) involves metabolic reprogramming, which consists of a deterioration in energy metabolism in the heart as a result of a mismatch between glucose uptake and its oxidation, leading to the accumulation of glucose-6-phosphate (G6P), glycogen and activation of the pentose phosphate pathway. This nutrient excess activates the mammalian target of rapamycin (mTOR), thereby promoting pathological myocardial remodeling, and at the same time suppresses the nutrient deficiency sensors SIRT1, AMPK and PGC-1α, which is accompanied by mitochondrial dysfunction, increased oxidative stress and decreased fatty acid oxidation. Similar processes occur in the proximal convoluted tubules of the kidneys in CKD, leading to renal dysfunction, albuminuria, and interstitial fibrosis. SGLT2 inhibitors inhibit the reabsorption of sodium and glucose in the proximal tubule, which leads to increased urinary glucose excretion and moderate osmotic diuresis and natriuresis. Nutrient deficiency resulting from glucose excretion promotes the activation of AMPK, which is involved in the regulation of mitochondrial biogenesis by stimulating PGC-1α, stimulates catabolic metabolism and activates autophagy by inhibiting mTORC1, which is accompanied by antiinflammatory effects, reduced oxidative stress and apoptosis and increased autophagy. These processes are accompanied by a decrease in blood pressure and a decrease in the load on the myocardium, with a simultaneous decrease in the tone of the sympathetic nervous system. Taking SGLT2 inhibitors is accompanied by normalization of tubuloglomerular feedback and a decrease in hyperfiltration, which has a beneficial effect on glomerular hemodynamics, as well as stimulation of erythropoiesis as a result of simulating systemic hypoxia. The described processes may serve as the basis for the cardioprotective and nephroprotective effects of SGLT2 inhibitors.