The hypoxia inducible factors (HIFs) regulate oxygen homeostasis by altering cell glucose metabolism (HIF-1α) and EPO production (HIF-2α). The two isoforms exert antagonistic effects on redox balance and pro-inflammatory/fibrotic pathways. We showed that high glucose (HG) induces HIF-1α in human endothelial cells by inhibiting prolyl hydroxylases D2 via methylglyoxal, leading to Warburg-like metabolic reprogramming, contributing to glucotoxicity. These findings have been validated in podocytes as well. Sirtuin1 (SIRT1), a low energy sensor, is suppressed in states of perceived nutrient excess (e.g., diabetes) and stimulated by energy deprivation signals (e.g., glucose loss with urine). Consistently, diabetes decreases, while SGLT2 inhibition (SGLT2i) promotes SIRT1 activity. SIRT1 also favors the protective activity of HIF-2α over the detrimental effects of HIF-1α. However, it is unclear whether SIRT1 activation and HIFs responses mediate SGLT2i’s protective effects in diabetic nephropathy. Here we investigate the role of HIF-1α in HG-induced tubular damage, the impact of HG on SIRT-1/HIFs axis, and the effect of SGLT2 inhibition on the changes induced by HG. To this aim, human Tubular Epithelial Cells (hTEC) were exposed to NG (5.5 mM) or HG (25 mM) for various times, silenced or not for HIF-1α (si-HIF-1α) and SGLT2 (si-SGLT2). In hTEC, as in podocytes, HG induced doubling of mRNA and nuclear protein levels of HIF-1α, thereby increasing its activity and interaction with pyruvate kinase M2, thus confirming a Warburg-like reprogramming. Consistently, HG increased mRNA levels of HIF-1α target genes endoglin and carbonic anhydrase IX. HG also upregulated the expression of mesenchymal markers such as fibronectin, vimentin, and α-SMA, while downregulating the expression of the epithelial marker E-cadherin, as demonstrated by PCR and IF analyses. These effects were prevented by si-HIF-1α. In addition to HIF-1α activation, HG caused significant decreases in HIF-2α mRNA and nuclear protein levels, as well as mRNA levels of the HIF-2α target gene HIF1AN, along with reduced SIRT1 expression. si-SGLT2 restored SIRT1 levels, preventing alterations in the balance of HIF-1α/HIF-2α triggered by HG and normalizing their transcriptional activity. This data demonstrates the involvement of HIF-1α in HG-induced tubular damage, indicating that HG favors HIF-1α over HIF-2α, possibly via reduced SIRT-1 activity, and that these effects were prevented by SGLT2 inhibition.