Pemolesatide Alleviates Kidney Injury in Diabetic Kidney Disease by Inhibiting Ferroptosis in Renal Tubular Epithelial Cells

Background: Pegoltesatide (PEG) is a novel long-acting peptide-based erythropoietin receptor agonist, clinically used to improve renal anemia in patients with chronic kidney disease. However, its effects beyond erythropoiesis remain unknown. Renal anemia is closely associated with disordered iron metabolism. In recent years, studies have reported that ferroptosis is involved in the progression of diabetic kidney disease (DKD), while the mechanisms remain unclear. We hypothesize that PEG play a role in regulating ferroptosis. This study aims to explore the effect of pemolesatide on renal injury in DKD and its mechanisms. Methods: HK-2 cells were divided into four groups: low glucose group (LG), high glucose group (HG), HG + PEG and HG + ferrostatin-1 (Fer-1) group . Cell viability was measured using the CCK-8 assay, apoptosis rate was detected by flow cytometry. The levels of ROS generation, iron content, MDA, and GSH/GSSG were assessed. The expression of GPX4, ALC7A11, TFR-1, and FTH-1 was examined using Western blotting. Results: The CCK-8 assay showed HG reduced the viability of HK-2 cells, while PEG significantly increased cell survival. Western blots revealed that HG stimulation upregulated the expression of renal injury markers KIM-1 and NGAL in HK-2 cells, whereas PEG or Fer-1 treatment downregulated their expression. HG stimulation also promoted apoptosis, increased ROS and MDA production, and iron levels in HK-2 cells. PEG or Fer-1 treatment effectively reduced apoptosis, suppressed ROS generation, and decreased MDA and iron accumulation. Additionally, HG exposure led to a decline in the GSH/GSSG ratio, which was rescued by PEG or Fer-1. Conclusion: Pemolesatide mitigates diabetic renal injury by suppressing HG-induced excessive ferroptosis in renal tubular epithelial cells. Funding: Government Support – Non-U.S.