Table 1.

Selected mechanisms of interactions between SGLT2 inhibitors, inflammation and oxidative stress.

	Inflammation	Oxidative Stress
	Kidney
SGLT2i	-Promote autophagic potential of renal cells (induction of AMPK phosphorylation AMPK) [24] -Decrease activity of mammalian target of rapamycin (mTOR) [24,68] -Decrease synthesis of proinflammatory cytokines: interleukin 1β (IL1β), interleukin 6 (IL6) and tumor necrosis factor α (TNFα) through inhibition of NF-κB [24,25,35,37,66,73,82] -Suppress p65 subunit of NF-κB, secondary to activation of AMPK [24,25,26,35] -Prevent expression of αSMA (alpha-smooth muscle actin), a marker of cell de-differentiation that inhibits changes of the phenotype of tubular cells into the proinflammatory and profibrotic [25] -Partially restore expression of pentraxin 3 (PTX 3) (PTX3 favorably attenuates inflammatory activity of macrophages, promotes M2 phenotype and downregulates NF-κB, IL1β, TNFα and monocyte chemoattractant protein 1 (MCP1)) [24,26,65] -Inhibit TRAF3IP2 (TRAF3-interacting protein 2), the proinflammatory protein induced by high glucose, activating IκB kinase (IKK)/NF-κB and promoting the expression of inflammatory mediators; prevent advanced glycation end-product-mediated stimulation of TRAF3IP2 expression [35] -Reduce activity of p38-MAPK [35] -Prevent high-glucose-induced synthesis and release of matrix metalloproteinase 2 (MMP2) [35] -Prevent upregulation of mesenchymal phenotype, i.e., αSMA, fibronectin and vimentin and downregulation of E- cadherin [35] -Reduce renal expression of mRNA of collagens type 1 and type 3 [37] -Decrease the activity of NLPR3 inflammasome and caspase-3 and increase the phosphorylated/total AMPK ratio [37,38,72] -Decrease caspase-1 activation [38]	-Prevent increase in reactive oxygen species [22] -Abolish the superoxide generation in tubular cells [35] -Augment the antioxidant defense mechanisms, activate AMPK, AKT serine/threonine kinase 1 (AKT1) and eNOS [39,72] -Prevent formation of advanced glycation and oxidation products [39] -Increase in β-hydroxybutyric acid (βOHB) [41]
	Other organs/tissues/cells
SGLT2i	-Liver: decrease the amount of MDA, interleukins 1β and 18 and TNFα [54,55,58] -Liver: promote autophagy, inhibit apoptosis and inflammation (by reducing mTOR signaling and MCP-1 expression) [57] -Liver and adipose tissue: decrease expression of mRNA for such mediators of p38-mitoge-activated protein kinase [p38-MAPK], NF-κB or extracellular signal-regulated kinase [ERK]) [66] -Adipose tissue: increase autophagic flux by upregulation of sirtuin 1 (SIRT1), fibroblast growth factor 21 (FGF-21) and peroxisome proliferator-activated receptor γ co-activator 1α (PGC1α); upregulation of SIRT1 leads to activation of hypoxia-inducible factor 2α (HIF2α) [60,61,62,63,64] -Adipose tissue: inhibit phosphorylation of NF-κB and signal transducer and activator of transcription (STAT) 1 and 3, Janus (JAK2) kinase and IKK [66] -Adipose tissue: downregulate IKK/NF-κb, MKK7/JNK and JAK2/STAT1 pathways [66] -Endothelial cells: inhibit hexokinase 2 (HK2) activation, HK2-mediated ERK1/2 phosphorylation and IL-6 synthesis and increase AMPK activation in LPS [76]	-Liver: reduced oxidative stress by means of decreased level of MDA and sustained enzymatic activity of superoxide dismutase [54,58] -Liver: prevent downregulation of Nrf2 and PPARγ (peroxisome proliferator-activated receptor gamma) mRNA [55,56] -Cardiomyocytes: augment nuclear factor erythroid 2-related factor 2/heme oxygenase 1 (Nrf2- and HO-1)-mediated antioxidant and anti-inflammatory signaling [40] -Cardiomyocytes: upregulate Nrf2/HO-1 (nuclear factor-erythroid 2 related factor/heme oxygenase 1) [68] -Cardiomyocytes: reduce concentration of H2O2, 3-nitrotyrosine and lipid peroxide in cytosol and mitochondria [43] -Cardiomyocytes: reduce oxidation of PKGIα protein kinase G type Iα, the cGMP-dependent protein kinase controlling the calcium flux within cells [43] -Adipose tissue: reduce 8-iso-prostaglandin F2α and 8-hydroxy-2′-deoxyguanosine [8-ohdg] [82]