Introduction:To maintain systemic homeostasis, albumin and lowmolecular-weight proteins filtered through the glomerulus are reabsorbed by proximal tubular epithelial cells (PTECs) through megalinmediated endocytosis, thereby preventing their urinary loss.Megalin, encoded by the Lrp2 gene, is an endocytic receptor expressed on the apical membrane of PTECs and plays a crucial role in reabsorbing biologically active molecules.Previous studies have reported both protective and detrimental effects of megalin on renal injury.For instance, megalin deficiency attenuates kidney injury in models of rhabdomyolysis-induced AKI and drug-induced nephrotoxicity (e.g., vancomycin), whereas it exacerbates renal injury in models of hemolysis-induced AKI and western diet-induced tubulointerstitial nephritis.Regarding ischemia-reperfusion injury (IRI), megalin mRNA expression decreases 24 hours after IRI and recovers by 96 hours; however, its pathophysiological role during the AKI phase and the AKI-to-CKD transition remains unclear.Methods: To elucidate the role of megalin in the AKI and AKI-to-CKD transition after IRI, we used male C57BL/6 mice and tamoxifeninducible PTEC-specific megalin knockout mice (Megalin fl/fl; Ndrg1-CreERT2; hereafter referred to as iMegKO).First, unilateral IRI (35 min) was performed in C57BL/6 mice to assess the temporal expression and function of megalin.Next, to investigate its role during the AKI phase, IRI was induced in iMegKO mice following three consecutive tamoxifen injections (AKI model).To explore its role during the AKI-to-CKD transition, tamoxifen was administered one and three days after IRI (AKI-to-CKD model).Results: In wild-type mice, megalin expression and function transiently decreased during the AKI phase after IRI and subsequently recovered.In the AKI model, renal injury in iMegKO mice was comparable to that in Megalin fl/fl controls.However, in the AKI-to-CKD model, iMegKO mice exhibited markedly exacerbated renal fibrosis, highlighting the critical role of megalin during the recovery phase.Single-cell transcriptomic analysis revealed that the expression of selenoprotein-related genes, which are involved in antioxidant and anti-inflammatory defense, was significantly downregulated in iMegKO kidneys.Given that selenoprotein P (SePP1) serves as a plasma selenium carrier and a ligand for megalin, we hypothesized impaired selenium uptake in iMegKO mice.Indeed, the expression of selenoproteins, including GPX4-a key ferroptosis regulator-was reduced in iMegKO mice after IRI.Treatment with the ferroptosis inhibitor liproxstatin-1 or selenium supplementation (sodium selenite) markedly ameliorated renal fibrosis in iMegKO mice.Conclusion: Megalin plays a pivotal role in protecting against renal fibrosis during the AKI-to-CKD transition by maintaining the selenoprotein P-GPX4-ferroptosis axis.Disruption of this pathway promotes ferroptotic injury and fibrotic remodeling after ischemic renal damage.I have no potential conflict of interest to disclose.I did not use generative AI and AI-assisted technologies in the writing process.
Lu et al. (Wed,) studied this question.