Overexpression of GPX4 in diabetic rat kidney alleviates renal injury induced by ferroptosis

Abstract

Ferroptosis-mediated injury in diabetic kidney (DKD) is receiving increasing attention. Glutathione Peroxidase 4 (GPX4) has long been considered a key protein to prevent ferroptosis, but its exact role in the progression of DKD, where this protein down-regulated, remains unclear. Thus, to clarify GPX4 in DKD progression, we have used adeno-associated viruses (AAVs) to overexpress it in kidneys of DKD rats. Streptozotocin (STZ)-induced DKD rats were injected once with GPX4-AAVs via tail vein. Renal function and kidney pathology were measured. Before and after treatment with GPX4-AAV, variations in kidney of ferroptosis-related indicators, such as GPX4, dihydroorotate dehydrogenase (DHODH), iron content, glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA), transferrin receptor 1 (TFR1), ferritin heavy chain (FTH), were monitored. The kidneys of STZ-treated rats showed reduced expression of GPX4, DHODH, GSH and SOD, increased expression of TFR1 and FTH, and higher levels of iron and MDA. Histopathology was consistent with renal fibrosis and thickened renal tubules. Changes were partly reversed after overexpression of GPX4, with decreased expression of FTH, together with reduced iron and MDA levels, although expression of TFR1, GSH and SOD showed no significant change. Renal function showed a lower urine protein–creatinine ratio, whereas the effect on renal fibrosis and thickened renal tubules was alleviated. Our study demonstrates that GPX4 is downregulated in DKD, and its AAV-mediated overexpression in kidney of DKD rats partly alleviates the diabetic kidney injury induced by ferroptosis.