Interplay of adenosine monophosphate‐activated protein kinase/sirtuin‐1 activation and sodium influx inhibition mediates the renal benefits of sodium‐glucose co‐transporter‐2 inhibitors in type 2 diabetes: A novel conceptual framework

Abstract

Long-term treatment with sodium-glucose co-transporter-2 (SGLT2) inhibitors slows the deterioration of renal function in patients with diabetes. This benefit cannot be ascribed to an action on blood glucose, ketone utilization, uric acid or systolic blood pressure. SGLT2 inhibitors produce a striking amelioration of glomerular hyperfiltration. Although initially ascribed to an action of these drugs to inhibit proximal tubular glucose reabsorption, SGLT2 inhibitors exert renoprotective effects, even in patients with meaningfully impaired levels of glomerular function that are sufficient to abolish their glycosuric actions. Instead, the reduction in intraglomerular pressures may be related to an action of SGLT2 inhibitors to interfere with the activity of sodium-hydrogen exchanger isoform 3, thereby inhibiting proximal tubular sodium reabsorption and promoting tubuloglomerular feedback. Yet, experimentally, such an effect may not be sufficient to prevent renal injury. It is therefore noteworthy that the diabetic kidney exhibits an important defect in adenosine monophosphateactivated protein kinase (AMPK) and sirtuin-1 (SIRT1) signalling, which may contribute to the development of nephropathy. These transcription factors exert direct effects to mute oxidative stress and inflammation, and they also stimulate autophagy, a lysosomally mediated degradative pathway that maintains cellular homeostasis in the kidney. SGLT2 inhibitors induce both AMPK and SIRT1, and they have been shown to stimulate autophagy, thereby ameliorating cellular stress and glomerular and tubular injury. Enhanced AMPK/SIRT1 signalling may also contribute to the action of SGLT2 inhibitors to interfere with sodium transport mechanisms.The dual effects of SGLT2 inhibitors on AMPK/SIRT1 activation and renal tubular sodium transport may explain the protective effects of these drugs on the kidney in type 2 diabetes. K E Y W O R D Sautophagy, diabetic nephropathy, sirtuin-1, sodium-glucose co-transporter-2 inhibitor

SGLT2 Inhibitor Empagliflozin and DPP4 Inhibitor Linagliptin Reactivate Glomerular Autophagy in db/db Mice, a Model of Type 2 Diabetes

“…Kidney macroautophagy is regulated by mammalian target of rapamycin (mTOR) [8,38,39], AMP-activated protein kinase (AMPK) [8], SIRT1 [8], Wnt/β-catenin [40], and TGF-β [41] signaling pathways. The downregulation of glomerular autophagy under hyperglycemic condition is considered a result of activation of mTOR pathway [8,42] or suppression of AMPK activity and SIRT1 signaling [37,43,44]. In our study, glomerular autophagy was related negatively to parameters of glycemic status, fructosamine and glycated albumin.…”

Mechanisms Leading to Differential Hypoxia-Inducible Factor Signaling in the Diabetic Kidney: Modulation by SGLT2 Inhibitors and Hypoxia Mimetics

“…Diabetes is perceived as a state of energy overabundance and thus SIRT1 and AMPK signaling is markedly impaired in glomeruli and renal tubules in the diabetic kidney. 46 The suppression of SIRT1/AMPK activation can directly promote mitochondrial dysfunction, oxidative stress, and proinflammatory pathways, 47,48 and downregulation of SIRT1/AMPK also eliminates a major stimulus to autophagic flux. 41,46 For these reasons, suppression of SIRT1/AMPK signaling and autophagy appear to contribute importantly to the pathogenesis of the glomerular and tubular lesions in diabetic nephropathy, 41,49,50 whereas AMPK/SIRT1 activation and promotion of autophagy leads to favorable effects on the development of CKD.…”

“…46 The suppression of SIRT1/AMPK activation can directly promote mitochondrial dysfunction, oxidative stress, and proinflammatory pathways, 47,48 and downregulation of SIRT1/AMPK also eliminates a major stimulus to autophagic flux. 41,46 For these reasons, suppression of SIRT1/AMPK signaling and autophagy appear to contribute importantly to the pathogenesis of the glomerular and tubular lesions in diabetic nephropathy, 41,49,50 whereas AMPK/SIRT1 activation and promotion of autophagy leads to favorable effects on the development of CKD. 51,52 It is therefore noteworthy that even in the presence of hypoxia, activation of both AMPK and SIRT1 inhibits HIF-1α (although studies in the kidney are limited).…”

“…56 Additionally, in type 2 diabetes, SGLT2 inhibitors act to enhance nutrient deprivation signaling as a result of their effect to promote the loss of calories in urine. 46,65 In doing so, SGLT2 inhibitors upregulate both AMPK and SIRT1, 46,65 which (in turn) act to suppress HIF-1α and activate HIF-2α. [53][54][55] Effect of Hypoxia Mimetics and Novel Prolyl Hydroxylase Inhibitors on HIF Signaling in the Diabetic Kidney Hypoxia mimetics enhance HIF-1α and/or HIF-2α activity, generally by inhibiting 1 or several of the 3 prolyl hydroxylases that are responsible for degradation of the isoforms.…”

The Off-Target Effects, Electrolyte and Mineral Disorders of SGLT2i

“…AMPK and SIRT signaling is also closely linked to sodium transport mechanisms, regulating the intracellular sodium. The activation of AMPK and SIRT1 lead to down-regulation of NHE and the epithelial sodium channel (ENaC), whose activity is enhanced in diabetes [31], and in this way induce a low intracellular sodium content, improving the antioxidative defense systems [32]. SGLT2 inhibitors lead to enhanced AMPK/SIRT1 signaling thus increasing authophagy and tubuloglomerular feedback both underpinning the SGLUTi protective effects on diabetic kidney disease [33].…”