Table 2.
Proposed hypotheses for the kidney protective mechanisms of SGLT2 inhibitors in DKD.
| Mechanisms | Ref. |
|---|---|
| decreased sodium uptake by Na+/H+ exchanger isoform 3 (NHE3) expression in proximal convoluted tubules (PTs) | (128–133) |
| reduced urinary excretion of angiotensin II and angiotensinogen levels in SGLT2 inhibitor-treated T2DM rats | (134) |
| did not further activate RAS in the long term, which prevented the RAS-mediated aggravation of cardiovascular and renal events | (134, 135) |
| reduced urinary angiotensinogen excretion in patients with T2DM | (136) |
| increased urinary angiotensinogen excretion in patients with T1DM | (137, 138) |
| modulated the tubular expression of proteins governing the medullary concentration activity, further had an effect on fluid and electrolyte balance | (139, 140) (132) |
| blocked the activation of the apoptotic-associated protein within PT cells | (141) |
| glomerular fibrosis or injury was not alleviated in SGLT2-knockout diabetic mice | (142) |
| modulated oxidative stress and intraglomerular inflammation and could thus alleviate renal fibrosis | (143) |
| alleviated the generation of vanin-1, the biomarker for oxidative stress within the kidney | (144) |
| lessened the epithelial-to-mesenchymal transition by modulating miR21 | (145) |
| alleviated renal fibrosis by lowering lipid accumulation-induced inflammation mediated by CD68 macrophages | (146) |
| activation of tubuloglomerular feedback: alleviated apoptosis by increasing autophagosomal formation within glomerular mesangial cells and podocytes | (147, 148) |
| anti-inflammatory effects: decreased the levels of several cytokines such as tumor necrosis factorα (TNFα), interleukin-6, high-sensitivity C-reactive protein, and leptin | (149, 150) |
| restored oxygen supply, thereby alleviating the metabolic stress state in the mitochondria and restoring the hematocrit level in patients with DM | (151, 152) |
| reduced ECM fibrosis by inflammation reduction and RAAS overactivation | (153) |
| the EPO-producing ability in patients with DM might be reversed after treatment with SGLT2i | (154) |
| suppressed HIF-1α-mediated metabolic switch from lipid oxidation to glycolysis in kidney tubule cells of diabetic mice. | (155) |
| inhibited aberrant glycolytic metabolism and mitochondrial ROS formation in PTEC in high-glucose conditions. | (156) |
| via the reduction of megalin O-GlcNAcylation and the following megalin internalization and endocytic functional suppression to attenuate protein overload in renal proximal tubule in progressive DKD. | (56) |
| promoted elevation of ketone bodies, which subsequently inhibited mTORC1 in the proximal renal tubules, explaining their protective effects s in non-proteinuric and proteinuric DKD. | (157) |
| Empagliflozin protected against proximal renal tubular cell injury induced by high glucose via regulation of hypoxia-inducible factor 1-alpha. | (158) |
NHE3, Na+/H+ exchanger isoform 3; PT, proximal convoluted tubule; SGLT2, sodium-glucose co-transporter 2; T1DM/T2DM, type 1/2 diabetes mellitus; RAS, renin-angiotensin system; RAAS, Renin-angiotensin-aldosterone System; TNFα, tumor necrosis factorα; ECM, extracellular matrix; EPO, erythropoietin; DM, diabetes mellitus; HIF-1α, hypoxia inducible factor-1α; PTEC, Proximal Tubular Epithelial Cell; DKD, Diabetic Kidney Disease; mTORC1, mammalian target of rapamycin complex 1.