Abstract
Previous studies have demonstrated intrarenal hypoxia in patients with diabetes. Hypoxia-inducible factor (HIF)-1 plays an important role in hypoxia-induced tubulointerstitial fibrosis. Recent clinical trials have confirmed the renoprotective action of SGLT2 inhibitors in diabetic nephropathy. We explored the effects of an SGLT2 inhibitor, luseogliflozin on HIF-1α expression in human renal proximal tubular epithelial cells (HRPTECs). Luseogliflozin significantly inhibited hypoxia-induced HIF-1α protein expression in HRPTECs. In addition, luseogliflozin inhibited hypoxia-induced the expression of the HIF-1α target genes PAI-1, VEGF, GLUT1, HK2 and PKM. Although luseogliflozin increased phosphorylated-AMP-activated protein kinase α (p-AMPKα) levels, the AMPK activator AICAR did not changed hypoxia-induced HIF-1α expression. Luseogliflozin suppressed the oxygen consumption rate in HRPTECs, and subsequently decreased hypoxia-sensitive dye, pimonidazole staining under hypoxia, suggesting that luseogliflozin promoted the degradation of HIF-1α protein by redistribution of intracellular oxygen. To confirm the inhibitory effect of luseogliflozin on hypoxia-induced HIF-1α protein in vivo, we treated male diabetic db/db mice with luseogliflozin for 8 to 16 weeks. Luseogliflozin attenuated cortical tubular HIF-1α expression, tubular injury and interstitial fibronectin in db/db mice. Together, luseogliflozin inhibits hypoxia-induced HIF-1α accumulation by suppressing mitochondrial oxygen consumption. The SGLT2 inhibitors may protect diabetic kidneys by therapeutically targeting HIF-1α protein.
Highlights
Diabetic nephropathy is the most common disease resulting in end-stage renal disease (ESRD)[1] and it is imperative to develop an effective treatment for diabetic nephropathy
We examined the effects of luseogliflozin on the expression of hypoxia-inducible factor (HIF)-1 target genes in human renal proximal tubular epithelial cells (HRPTECs) (Fig. 1b–f)
We demonstrated that luseogliflozin inhibited hypoxia-induced nuclear HIF-1α expression and HIF-1 target genes in HRPTECs (Fig. 1a)
Summary
Diabetic nephropathy is the most common disease resulting in end-stage renal disease (ESRD)[1] and it is imperative to develop an effective treatment for diabetic nephropathy. SGLT2 inhibitors are recommended as a second-line medication for patients with atherosclerotic cardiovascular disease or chronic kidney diseases for the management of type 2 diabetes[6]. The mechanisms of how SGLT2 inhibitors prevent diabetic nephropathy, especially their direct effect on proximal tubular cells, have not been fully elucidated. Hypoxia status of renal tubular cells is known to cause fibrosis in diabetic kidney[7]. Diabetes increased HIF1ααexpression in proximal tubular cells in a type 2 diabetic animal model with nephropathy[12,13] and in renal tissues from patients with diabetic nephropathy[14]. Plasminogen activator inhibitor-1 (PAI-1), a major HIF-1 target gene, is an important factor for the progression of kidney fibrosis, and previous studies showed that genetically silencing Pai-1 alleviates diabetic nephropathy in mice[19,20]. There is no clinical treatment targeting renal hypoxia in diabetic nephropathy to date
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