Empagliflozin Attenuates Renal Tubular Ferroptosis in Preeclampsia via Tazarotene-Induced Gene 1.

Abstract

Preeclampsia (PE) is a serious pregnancy complication characterized by elevated blood pressure and a major cause of maternal and perinatal morbidities, also known to increase the risk of chronic kidney disease. Mechanisms underlying PE-induced kidney injury remain unclear. Anti-angiotensin II type 1 receptor agonistic autoantibody (AT1-AA) is reported to participate in the pathogenesis of PE-induced kidney injury. Our previous study replicated the major features of PE in pregnant mice by administration of intravenous injection of AT1-AA and found that podocyte senescence plays a role in PE-induced kidney injury. Elevated levels of N-acetyl-β-D glucosaminidase (NAG) and kidney injury molecule-1 (KIM-1) in the urine of patients with PE have been reported, indicating renal tubular injury. In this study, we identified the role of renal proximal tubular epithelial cells (PTECs) in PE-induced kidney injury and the therapeutic value of empagliflozin, an anti-diabetic agent, in a murine model of AT1-AA-induced PE. In our study, higher tubular injury score (Control vs. PE: P<0.0001) show that PTECs are damaged in AT1-AA-induced PE. We identified ferroptosis as one of the cause of AT1-AA-induced PTEC injury by RNAseq, and confirmed the involvement of ferroptosis by detecting ferrous iron (Control vs. PE: P<0.0001), reduced glutathione (GSH) (Control vs. PE: P<0.0001) and lipid peroxidation (Control vs. PE: P<0.0001). Empagliflozin ameliorates AT1-AA-induced PTEC ferroptosis and injury in PE. Furthermore, we demonstrated that tazarotene-induced gene 1 is involved in AT1-AA-induced PTEC injury. These findings suggest that renal tubules are injured in PE and empagliflozin has therapeutic potential for PE-induced PTEC injury.