Table 1.

Potential Mechanisms of Action of SGLT2 Inhibitors in the Cardio-Renal Physiology

Kidney	Heart
Regulation of cellular stress mediated by energy unbalance (reduction of ATP-dependent sodium/glucose uptake)	Regulation of cellular stress mediated by energy unbalance. Adaptation to alternative energy fuels (e.g. fatty acids)
Reduction of reactive oxygen species and markers of cellular injury in diabetic kidney disease.	Reduction of reactive oxygen species and markers of cellular injury during myocardial infarction and heart failure.
Downregulation of PKC, mTOR and TGF-β related-pathways. Reductions in fibrosis and inflammatory cytokines.	Modulation of JAK-STAT signaling pathways during ischemia-reperfusion injury, AMPK amplification, NHE1 inhibition.
Reduction in albuminuria, natriuresis, modulation of TGF and decrements in the rate of GFR decline	Blood pressure and weight reductions
Decrease cellular hypoxia, increments of hematocrit and restoration of EPO producing macrophages	Diuretic effect, and volume reduction. Greater benefit when associated with ACEi/ARBs

Abbreviations: ATP, adenosine-triphosphate; PKC, protein-kinase C; mTOR, mammalian target of rapamycin; TGF-β, transforming growing factor β; JAK-STAT, Janus kinase (JAK)-signal transducer and activator of transcription; AMPK, adenosine monophosphate activated protein kinase; NHE1, sodium-hydrogen exchanger 1; TGF, tubuloglomerular feedback; GFR, glomerular filtration rate; EPO, erythropoietin; ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blockers.