Ferroptosis Is Involved in the Process of Diabetic Kidney Disease

Background: Diabetic kidney disease(DKD) is a major public health problem that threatens human health and causes substantial economic burden. DKD is accompanied by accumulation of ROS and iron in the kidney, a hallmark of ferroptosis. Ferroptosis is a condition that causes cell death by accumulation of lipid reactive oxygen species (ROS), in an iron-dependent mechanism that is different from apoptosis, necroptosis and autophagy. That ferroptosis is involved in DKD has been shown recently, but its role is still unknown. Methods: We induced diabetic kidney disease in 8-week-old male rats with streptozotocin (STZ) and treated with ferroptosis inhibitor Fer-1 to analyze the degree of renal injury and the related indexes of ferroptosis. Results: 1. Diabetic renal injury involves ferroptosis. Accumulation of iron was also confirmed by Prussian blue staining and presented morphological changes linked to ferroptosis in DKD group: reduced mitochondrial volume, ruptured mitochondrial membrane and missing mitochondrial cristae. 2. Blocking ferroptosis can alleviate proteinuria and renal tubular injury in STZ-induced DKD. Fer-1 treatment clearly decreased the urine protein-creatinine ratio, both α-1 microglobulin and N-acetyl-β-D-glucosaminosidase in DKD group and the levels of both MDA and Fe2+. In addition, treating DKD rats with Fer-1 reduced iron in the kidney and alleviated kidney fibrosis. Conclusions: Ferroptosis is involved in the process of diabetic kidney disease. Markers of renal tubular injury α 1-microglobulin and N-acetyl-β-D-glucosaminosidase measured in urineFig 1.: Ferrostatin-1 (Fer-1) alleviates proteinuria and renal injury in DKD rats. Levels of serum glucose (A), blood urea nilrogen (B), urine protein-to-creatinine ratio (C), serum creatinine (D), renal MDA (E) and renal non-herne Iron (F) measured for 10 weeks after rats were injected with STZ (n=5). - Group (n=5) α1-microglobulin (mg/L) N-acetyl-β-D-glucosaminosidase (U/mmol creatinine) Control < 6.35 0.736±0.12 DN 7.54±1.19 2.24±0.96* DN+Fer-1 < 6.35 0.94±0.67*