Background. Diabetic kidney disease (DKD) represents a heavy burden in type 2 diabetes mellitus (T2DM). Ferroptosis plays an important role in DKD, and it thus provides new perspectives to pursue more related biomarkers to assess the disease severity and prognosis. Glutathione peroxidase 4 (GPX4) is the mainstay in regulating ferroptosis. The current study investigated the predictive value of kidney GPX4 expression level in DKD progression. Methods. We measured GPX4 levels in kidney paraffin sections of 85 biopsy-proven DKD patients by immunohistochemistry staining. The associations between the GPX4 level and clinicopathological parameters as well as renal outcomes were analyzed. Results. GPX4 is mainly expressed in kidney tubulointerstitium, especially in tubular epithelial cells of DKD patients. The GPX4 expression level was significantly lower in DKD patients than healthy controls. Besides, GPX4 level significantly correlated with proteinuria ( r = − 0.42 , p < 0.001 ), urinary albumin-to-creatinine ratio (uACR) ( r = − 0.40 , p < 0.01 ), serum creatinine (Scr) ( r = − 0.59 , p < 0.001 ), estimated glomerular filtration rate (eGFR) ( r = 0.66 , p < 0.001 ), and the percentage of sclerosed glomeruli ( r = − 0.42 , p < 0.001 ) in renal specimens. During follow-up, the GPX4 level positively correlated with eGFR slope ( r = 0.48 , p < 0.001 ), and GPX4-low patients showed a significantly higher probability of developing end-stage kidney disease (ESKD) compared with GPX4-high patients ( p < 0.01 ). Moreover, after adjusting for other potential predictors, the GPX4 level was still an independent predictor of developing ESKD (HR 2.15, 95% CI 1.08 to 4.28, p < 0.05 ). Conclusions. Kidney tubulointerstitial GPX4 expression level was associated with the disease severity and progression of DKD.

Background: Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease. In recent clinical trials, sodium-glucose cotransporter 2 inhibitors (SGLT2i) showed excellent renoprotection effects, but the underlying mechanism remains to be investigated. Previous studies have revealed an important role of ferroptosis, which is mediated by iron overload and lipid peroxidation, in the progression of DKD. Therefore, it is of interest to explore the effects of SGLT2i on ferroptosis in DKD due to its role in alleviating oxidative stress.Methods: Diabetic (db/db) mice were administered with dapagliflozin or solvent treatment from 9 to 22 weeks of age, and were compared with non-diabetic (m/m) mice. High glucose/high fat (HG/HF) was applied to HK-2 cells, and effects of dapagliflozin on ferroptosis in HK-2 cells as well as the underlying mechanism were investigated.Results: Typical changes of ferroptosis including massive lipid peroxidation, reduced antioxidant capability, and iron overload were found in db/db mice and HG/HF treated HK-2 cells. Furthermore, increased expression of hypoxia‐inducible factor‐1α (HIF‐1α) and heme oxygenase-1 (HO1) was observed in db/db mice and HG/HF cultured cells as well. Dapagliflozin treatment significantly ameliorated the ferroptosis-related changes via inhibiting HIF‐1α/HO1 axis in vivo and in vitro. Besides, downregulation of HIF‐1α/HO1 axis rescued ferroptosis, while overexpression of HO1 aggravated ferroptosis induced by HG/HF in HK-2 cells. In DKD patients, the expression level of GPX4 in the kidney was significantly lower than that in healthy controls.Conclusion: SGLT2i play a renal protective effect, at least in parts, via inhibiting HIF‐1α/HO1 axis mediated ferroptosis.

Background: Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease. In recent clinical trials, sodium-glucose cotransporter 2 inhibitors (SGLT2i) showed excellent renoprotection effects, but the underlying mechanism remains to be investigated. Previous studies have revealed an important role of ferroptosis, which is mediated by iron overload and lipid peroxidation, in the progression of DKD. Therefore, it is of interest to explore the effects of SGLT2i on ferroptosis in DKD due to its role in alleviating oxidative stress.Methods: Diabetic (db/db) mice were administered with dapagli ozin or solvent treatment from 9 to 22 weeks of age, and were compared with non-diabetic (m/m) mice. High glucose/high fat (HG/HF) was applied to HK-2 cells, and effects of dapagli ozin on ferroptosis in HK-2 cells as well as the underlying mechanism were investigated.Results: Typical changes of ferroptosis including massive lipid peroxidation, reduced antioxidant capability, and iron overload were found in db/db mice and HG/HF treated HK-2 cells. Furthermore, increased expression of hypoxia-inducible factor-1α (HIF-1α) and heme oxygenase-1 (HO1) was observed in db/db mice and HG/HF cultured cells as well. Dapagli ozin treatment signi cantly ameliorated the ferroptosis-related changes via inhibiting HIF-1α/HO1 axis in vivo and in vitro. Besides, downregulation of HIF-1α/HO1 axis rescued ferroptosis, while overexpression of HO1 aggravated ferroptosis induced by HG/HF in HK-2 cells. In DKD patients, the expression level of GPX4 in the kidney was signi cantly lower than that in healthy controls.Conclusion: SGLT2i play a renal protective effect, at least in parts, via inhibiting HIF-1α/HO1 axis mediated ferroptosis.