Glutathione Peroxidase 4 Is a Predictor of Diabetic Kidney Disease Progression in Type 2 Diabetes Mellitus

Abstract

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.