Sodium–glucose cotransporter 2 inhibition suppresses HIF-1α-mediated metabolic switch from lipid oxidation to glycolysis in kidney tubule cells of diabetic mice

Abstract

Inhibition of sodium–glucose cotransporter 2 (SGLT2) in the proximal tubule of the kidney has emerged as an effective antihyperglycemic treatment. The potential protective role of SGLT2 inhibition on diabetic kidney disease (DKD) and underlying mechanism, however, remains unknown. In this study, metabolic switch was examined using kidney samples from human with diabetes and streptozocin (STZ)-induced experimental mouse model of diabetes treated with or without SGLT2 inhibitor dapagliflozin. Results were further validated using primarily cultured proximal tubule epithelial cells. We found that DKD development and progression to renal fibrosis entailed profound changes in proximal tubule metabolism, characterized by a switch from fatty acid utilization to glycolysis and lipid accumulation, which is associated with the increased expression of HIF-1α. Diabetes-induced tubulointerstitial damage, such as macrophage infiltration and fibrosis, was significantly improved by dapagliflozin. Consistent with the effects of these beneficial interventions, the metabolic disorder was almost completely eliminated by dapagliflozin. The increased level of HIF-1α in renal proximal tubule was nearly nullified by dapagliflozin. Moreover, dapagliflozin protects against glucose-induced metabolic shift in PTCs via inhibiting HIF-1α. It suggests that SGLT2 inhibition is efficient in rectifying the metabolic disorder and may be a novel prevention and treatment strategy for kidney tubule in DKD.

Update on the Mechanisms of Tubular Cell Injury in Diabetic Kidney Disease

“…With increased oxygen utilization, hypoxia inducible factor (HIF)-1 α has been implicated in the correlation of hypoxic and tubulointerstitial fibrosis ( 26 – 30 ). On the other hand, SGLT-2 inhibitors have been shown to poses a renal protective effect on diabetes patients by inhibiting glucose reabsorption and its associated high oxygen consumption ( 21 , 31 ), in addition to targeting HIF-1 α protein to inhibit mitochondria oxygen consumption ( 32 , 33 ). Furthermore, these factors inhibit and internalize megalin O-GlcNAcylation to reduce the reabsorption of plasma proteins (e.g., albumin and neutrophil gelatinase-associated lipoprotein) in PT, which is renal protective ( 34 ).…”

“…However, in diabetics, the utilization of fatty acid is changed to glycolysis and lipid accumulation, which also represents an important pathway of DKD due to lipid accumulation in the renal tubular epithelia ( 83 ) via increased absorption and synthesis of fatty acids, in addition to decreased utilization. The toxic effect of FA on the renal tubular epithelial cells is associated with hypoxia and mitochondrial dysfunction ( 33 , 84 ). A recent study has shown that FATP2, a member of the fatty acid transporter family, regulates DKD pathogenesis through a combined lipotoxicity and glucotoxicity (glucolipotoxicity) mechanism ( 85 ).…”

Endogenous Fructose Metabolism Could Explain the Warburg Effect and the Protection of SGLT2 Inhibitors in Chronic Kidney Disease

“…SGLT2 inhibitors have recently received an attention from clinicians and researchers for their major therapeutic benefits that extend beyond its glycemic control in both non-diabetic and diabetic kidney diseases and in the cardiovascular complications associated to CKD ( 53 , 54 ). While the precise mechanisms remain unclear, recent studies have indicated that the protective effects might be accounted for by the prevention of the metabolic switch form lipid oxidation to glycolysis as aberrant glycolysis was likely associated with epithelial-to-mesenchymal transformation of proximal tubule cells in diabetic nephropathy ( 55 , 56 ). In addition, SGLT2 inhibitors may reduce intra-renal work by blocking glucose uptake, and thereby reducing intra-renal hypoxia with the blocking of HIF-1α accumulation, and with the preventing a reduction of klotho, events that are expected to reduce glycolysis ( 57 , 58 ).…”

Pathogenesis of diabesity‐induced kidney disease: role of kidney nutrient sensing

“…Several reports suggested that metabolic reprogramming in the kidney is mediated via HIF [164]. HIF1α is regulated by oxygen-dependent posttranslational hydroxylation by prolyl hydroxylase domain-containing (PHD-containing) enzymes.…”

“…HIF1α is regulated by oxygen-dependent posttranslational hydroxylation by prolyl hydroxylase domain-containing (PHD-containing) enzymes. Exposure to hypoxia or acute druginduced kidney injury, which markedly increases oxygen demand along with impairment of mitochondrial function leads to stabilization and nuclear transport of HIF1, which in turn induces metabolic shift from oxidative phosphorylation to glycolysis [164]. Of note, failure to inhibit glycolysis during the recovery phase after acute kidney injury was associated with tubular atrophy [165], suggesting that metabolic shift to glycolysis is a general response of the KPTC to stress that drives kidney dysfunction in diabetic and non-diabetic kidney disease.…”