Interplay Between Intracellular Iron Dysregulation and SGLT2 in Diabetic Proximal Tubulopathy

Background: Tubulointerstitial abnormalities are a crucial feature of diabetic nephropathy (DN) and a predictor of the progression of renal dysfunction. Ferroptosis, an iron-dependent form of regulated cell death, which involves intracellular iron accumulation, has become increasingly recognized as an important mediator of the pathogenesis of diabetic proximal tubulopathy (DPT), and sodium–glucose transport protein (SGLT)2 inhibition has been demonstrated to ameliorate tubular ferroptosis. The purpose of the present study was to clarify the mechanisms of intracellular iron dysregulation in DPT and explore the involvement of SGLT2 in these processes. Methods: We isolated proximal tubules from control and db/db mice, a model of type 2 DN, and measured the expression of iron import proteins (transferrin receptor 1 [TfR1] and divalent metal transporter 1 [DMT1]) and an iron export protein (ferroportin 1 [FP1]). We also evaluated the binding of iron regulatory protein (IRP) to iron-responsive element (IRE) motifs on the mRNAs for these iron transporters. These facilitate the translation of iron import proteins and inhibit that of iron export proteins by modulating mRNA stability. Finally, we evaluated the effect of SGLT2 inhibition on the intracellular iron regulation in DPT. Results: The proximal tubules from the mice exhibited high expression of TfR1 and DMT1 and low expression of FP1 at the mRNA and protein levels vs. the control mice. These differences in expression were determined at the posttranscriptional level and were associated with modifications of the IRE–binding activity of IRP. SGLT2 inhibition ameliorated the diabetes-induced dysregulation of the iron transporters and posttranscriptional regulation in the proximal tubules. Conclusion: The diabetes-induced proximal tubular dysregulation of iron transporters, which is mediated at least in part through an SGLT2-dependent pathway, could cause intracellular iron sequestration, which may play an important role in the pathophysiology of DTN.