Scavenger Receptor Class B Type I Deficiency Induces Iron Overload and Ferroptosis in Renal Tubular Epithelial Cells <i>via</i> Hypoxia-Inducible Factor-1α/Transferrin Receptor 1 Signaling Pathway

Abstract

<b><i>Aims:</i></b> Scavenger receptor class B type I (SRBI) promotes cell cholesterol efflux and the clearance of plasma cholesterol. Thus, <i>SRBI</i> deficiency causes abnormal cholesterol metabolism and hyperlipidemia. Studies have suggested that ferroptosis is involved in lipotoxicity; however, whether <i>SRBI</i> deficiency could induce ferroptosis remains to be investigated. <b><i>Results:</i></b> We knocked down or knocked out SRBI in renal HK-2 cells and C57BL/6 mice to determine the expression levels of ferroptosis-related regulators. Our results demonstrated that <i>SRBI</i> deficiency upregulates transferrin receptor 1 (TFR1) expression and downregulates ferroportin expression, which induces iron overload and subsequent ferroptosis in renal tubular epithelial cells. TFR1 is known to be regulated by hypoxia-inducible factor-1α (HIF-1α). Next, we investigated whether <i>SRBI</i> deletion affected HIF-1α. SRBI deletion upregulated the mRNA and protein expression of HIF-1α, and promoted its translocation to the nucleus. To determine whether HIF-1α plays a key role in <i>SRBI</i>-deficiency-induced ferroptosis, we used HIF-1α inhibitor and siHIF-1α in HK-2 cells, and found that downregulation of HIF-1α prevented SRBI-silencing-induced TFR1 upregulation and iron overload, and eventually reduced ferroptosis. The underlying mechanism of HIF-1α activation was explored next, and the results showed that SRBI knockout or knockdown may upregulate the expression of HIF-1α, and promote HIF-1α translocation from the cytoplasm into the nucleus <i>via</i> the PKC-β/NF-κB signaling pathway. <b><i>Innovation and Conclusion:</i></b> Our study showed, for the first time, that <i>SRBI</i> deficiency induces iron overload and subsequent ferroptosis <i>via</i> the HIF-1α/TFR1 pathway.