Abstract

The endoplasmic reticulum (ER) stress and mitochondrial dysfunction in high glucose (HG)-induced podocyte injury have been demonstrated to the progression of diabetic kidney disease (DKD). However, the pathological mechanisms remain equivocal. Mitofusin2 (Mfn2) was initially identified as a dynamin-like protein involved in fusing the outer mitochondrial membrane (OMM). More recently, Mfn2 has been reported to be located at the ER membranes that contact OMM. Mitochondria-associated ER membranes (MAMs) is the intercellular membrane subdomain, which connects the mitochondria and ER through a proteinaceous tether. Here, we observed the suppression of Mfn2 expression in the glomeruli and glomerular podocytes of patients with DKD. Streptozotocin (STZ)-induced diabetic rats exhibited abnormal mitochondrial morphology and MAMs reduction in podocytes, accompanied by decreased expression of Mfn2 and activation of all three unfolded protein response (UPR) pathways (IRE1, ATF6, and PERK). The HG-induced mitochondrial dysfunction, MAMs reduction, and increased apoptosis in vitro were accompanied by the downregulation of Mfn2 and activation of the PERK pathway. Mfn2 physically interacts with PERK, and HG promotes a decrease in Mfn2-PERK interaction. In addition, Mfn2-silenced podocytes showed mitochondrial dysfunction, MAMs reduction, activation of PERK pathway, and increased apoptosis. Conversely, all these effects of HG stimulation were alleviated significantly by Mfn2 overexpression. Furthermore, the inhibition of PERK phosphorylation protected mitochondrial functions but did not affect the expression of Mfn2 in HG-treated podocytes. Therefore, this study confirmed that Mfn2 regulates the morphology and functions of MAMs and mitochondria, and exerts anti-apoptotic effects on podocytes by inhibiting the PERK pathway. Hence, the Mfn2-PERK signaling pathway may be a new therapeutic target for preventing podocyte injury in DKD.

Highlights

  • With the increase in incidences of diabetes mellitus (DM), diabetic kidney disease (DKD) has become a public health issue, which is the leading cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD) (Umanath and Lewis, 2018)

  • The transmission electron microscope (TEM) analysis of glomerular podocytes demonstrated mitochondrial fragmentation and Mitochondria-associated ER membranes (MAMs) reduction in the diabetic rats compared with those in the controls, which indicated elongated mitochondria and abundant contact points localized at the interface of the endoplasmic reticulum (ER) and outer mitochondrial membrane (Supplementary Figures 1B–D)

  • Flow cytometry examined cell apoptosis and showed that high glucose (HG) significantly provokes podocyte apoptosis (Figures 4M, N). These findings demonstrated that ER stress was associated with the progression of glomerular damage and podocyte injury in DKD, and activation of the protein kinase RNA-like ER kinase (PERK) pathway may be the key factor of podocyte apoptosis in DKD

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Summary

Introduction

With the increase in incidences of diabetes mellitus (DM), DKD has become a public health issue, which is the leading cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD) (Umanath and Lewis, 2018). Podocyte injury and loss have been well demonstrated to be correlated with proteinuria and renal function deterioration, they are considered to be the key events in the progression of DKD, but their pathological mechanisms have not yet been elucidated. The mitochondrial dysfunction and ER stress have drawn the attentions, which are closely related to podocyte injury and apoptosis in DKD (Chen et al, 2020; Cybulsky, 2010; Fan et al, 2019). Given the crucial roles of ER stress and mitochondrial dysfunction, it is imperative to reveal the underlying mechanisms through which MAMs evolve and affect the injury and apoptosis of podocyte in diabetic kidneys

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