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.

Role of ferroptosis inhibitors in the management of diabetes

“…24 Wang et al showed that in T2DM patients Gpx4 levels are lowered, and this led to the development of diabetic kidney disease (DKD) in these patients. 60 Interestingly, reduced Gpx4 levels correlated with an elevation in proteinuria, albumin-to-creatinine ratio, serum creatinine, and sclerosed glomeruli percentage in these diabetic patients. Notably, patients with lower Gpx4 had a higher risk of onset of end-stage kidney disease, compared to diabetic patients with higher Gpx4 levels.…”

“…Notably, patients with lower Gpx4 had a higher risk of onset of end-stage kidney disease, compared to diabetic patients with higher Gpx4 levels. 60 Another study depicts the reduced levels of Gpx4 in kidney biopsy samples of T2DM patients and suggests the role of ferroptosis in kidney tubular cell death in diabetes patients. 24 Moreover, in diabetic mice, the kidney protein levels of both XcT and Gpx4 were markedly reduced, followed by subsequent GSH depletion and lipid ROS-mediated ferroptotic cell death.…”

“…Analysis of kidney biopsy samples obtained from diabetic patients revealed a reduced expression of system Xc T and GPX4 mRNA than healthy controls 24 . Wang et al showed that in T2DM patients Gpx4 levels are lowered, and this led to the development of diabetic kidney disease (DKD) in these patients 60 . Interestingly, reduced Gpx4 levels correlated with an elevation in proteinuria, albumin‐to‐creatinine ratio, serum creatinine, and sclerosed glomeruli percentage in these diabetic patients.…”

Antioxidant Phytochemicals as Potential Therapy for Diabetic Complications

“…Wang et al [135] reported on the role of kidney GPx4 expression level in DN progression. The GPx4 expression level was significantly lower in DN patients than in healthy controls and was associated with disease severity and progression [135].…”

“…Wang et al [135] reported on the role of kidney GPx4 expression level in DN progression. The GPx4 expression level was significantly lower in DN patients than in healthy controls and was associated with disease severity and progression [135]. Similarly, mice with DN showed significant changes in ferroptosis-associated markers such as increased expression levels of acyl-CoA synthetase long-chain family member 4 (ACSL4) and decreased expression levels of GPx4 [136].…”