SGLT2 Inhibitors Enhance Metallothionein Expression in Kidney Proximal Tubules of Adolescents With Type 2 Diabetes

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Background: Oxidative stress is a main contributor to diabetic kidney disease (DKD), and SGLT2 inhibitors (SGLT2i) mitigate DKD onset in type 2 diabetes (T2D). An investigation of cell-type specific molecular reprogramming in the kidney with SGLT2i treatment was undertaken in young persons with T2D. Methods: Single-cell RNA sequencing (scRNAseq) profiles of young persons (17±2 years) with T2D, treated with SGLT2i (N=10, T2Di+) or not (N=6, T2Di-), and healthy controls (N=6, HC) were obtained from protocol kidney biopsies. Similarly derived scRNAseq data were available for living donors (N=20, LD), T2D Pima Indians with DKD (N=42), and Kidney Precision Medicine Project (N=12) cohorts. Analysis of scRNAseq data identified differentially expressed genes (DEGs). enrichR enabled pathway enrichment analysis of DEGs. Results: All participants had normal to elevated GFR by iohexol clearance (185-224 ml/min). Similar occurrence of microalbuminuria (˜20%) but lower HbA1c (6.1% vs. 7.3%) were observed in T2Di- compared to T2Di+ at screening. In the proximal tubular (PT) cluster (10,032 cells), 1003 genes elevated in T2Di- vs. HC were suppressed by SGLT2i (T2Di+ vs. T2Di-) while 176 repressed transcripts in T2Di+ were recovered with SGLT2i. Most metabolic pathways increased in T2Di- were suppressed in PT by SGLT2i, except metallothionein and insulin receptor signaling pathways, which were enhanced with SGLT2i exposure (p<0.05). Repression of metallothioneins in PT could be validated in two independent DKD cohorts (Fig.1).Fig. 1:: Diabetes-associated down-regulation of MT genes in three cohorts (T2D, Pima Indians, KPMP). Treatment with SGLT2i (T2Di) in the youth onset T2D cohort, showed enhanced expression of MT genes relative to T2D. Abbreviations; MT-metallothionein, T2D-type 2 diabetes; LD-living donors; KPMP- Kidney Precision Medicine Project; SGLT2i-sodium-glucose cotransporer-2 inhibitors, IogFC-log2 fold change.Conclusions: SGLT2i treatment may rescue metallothionein expression in PT, consistent with a more favorable redox state. Funding: NIDDK Support

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