SGLT2 Inhibitors Attenuate Hypoxia and HIF1A Expression in Young Persons With Type 2 Diabetes

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Background: SGLT2 inhibitors (SGLT2i) are protective in diabetic kidney disease. Their potential impact on kidney oxygenation and transcriptional responses to hypoxia were assessed. Methods: Blood oxygen level dependent-MRI data were available in young persons with type 2 diabetes (T2D, n=22, 13 on SGLT2i). Single-cell RNA sequencing data were generated from research kidney biopsies in a subset of T2D (n=16, 10 on SGLT2i) and healthy controls (HC, n=6) and compared to tubulointerstitial microarray data from kidney biopsies of American Indians with T2D (n=47). The transcriptional profile of Hypoxia Response Genes (HRG), comprising 172 target genes of Hypoxia Inducible Factor-1A (HIF1A), were examined in HC and T2D, with and without SGLT2i. Results: The average (SD) age of participants with T2D was 16±2 years and median (IQR) measured GFR was 185 (160-242) ml/min. Higher cortical and medullary oxygen availability was associated with SGLT2i treatment (Fig.1). Increased HIF1A expression in T2D (without SGLT2i) compared to HC in proximal tubules (PT) was suppressed with SGLT2i. Correspondingly, 27% of HRG was suppressed with SGLT2i in PT, with glycolytic enzymes including phosphoglycerate kinase (PGK1) and phosphofructokinase (PFKL) as major contributors. PGK1 (r=0.53, p<0.05) and PFKL (r=0.58, p<0.05) expression, rather than HIF1A, in PT cells correlated with increased cortical hypoxia (higher R2*). In American Indians with T2D, increased HIF1A expression was associated with increased interstitial fibrosis (r=0.47, p<0.05) and future loss of kidney function (r=-0.44, p<0.05).Fig. 1.: Lower hypoxia in kidneys with SGLT2 inhibitor treatmentConclusions: SGLT2i associate with improved kidney oxygenation, which may mitigate the deleterious morphometric and clinical outcomes associated with high kidney HIF1A expression and contribute to the beneficial kidney effects of SGLT2i. Funding: NIDDK Support

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