Podocyte Injury in Diabetic Kidney Disease: A Focus on Mitochondrial Dysfunction

Abstract

Podocytes are a crucial cellular component in maintaining the glomerular filtration barrier, and their injury is the major determinant in the development of albuminuria and diabetic kidney disease (DKD). Podocytes are rich in mitochondria and heavily dependent on them for energy to maintain normal functions. Emerging evidence suggests that mitochondrial dysfunction is a key driver in the pathogenesis of podocyte injury in DKD. Impairment of mitochondrial function results in an energy crisis, oxidative stress, inflammation, and cell death. In this review, we summarize the recent advances in the molecular mechanisms that cause mitochondrial damage and illustrate the impact of mitochondrial injury on podocytes. The related mitochondrial pathways involved in podocyte injury in DKD include mitochondrial dynamics and mitophagy, mitochondrial biogenesis, mitochondrial oxidative phosphorylation and oxidative stress, and mitochondrial protein quality control. Furthermore, we discuss the role of mitochondria-associated membranes (MAMs) formation, which is intimately linked with mitochondrial function in podocytes. Finally, we examine the experimental evidence exploring the targeting of podocyte mitochondrial function for treating DKD and conclude with a discussion of potential directions for future research in the field of mitochondrial dysfunction in podocytes in DKD.

LRH‐1 activation alleviates diabetes‐induced podocyte injury by promoting GLS2‐mediated glutaminolysis

“…20 Emerging data from epidemiologic analyses, experimental studies, and clinical trials indicate DKD as a metabolic disorder, and the metabolic reprogramming of podocytes contributes to the pathogenesis of DKD. 21,22 Thus, targeting the metabolic pathways of podocytes is a promising therapeutic approach for DKD. In the current study, we revealed that LRH-1 positively modulated the Gln metabolism in podocytes.…”

“…DKD has become a significant cause of chronic kidney disease (CKD) and end‐stage renal disease (ESRD) 20 . Emerging data from epidemiologic analyses, experimental studies, and clinical trials indicate DKD as a metabolic disorder, and the metabolic reprogramming of podocytes contributes to the pathogenesis of DKD 21,22 . Thus, targeting the metabolic pathways of podocytes is a promising therapeutic approach for DKD.…”

Qing-Re-Xiao-Zheng-Yi-Qi formula relieves kidney damage and activates mitophagy in diabetic kidney disease

“…Podocytes are rich in mitochondria and rely on them for energy to maintain normal functions. Mitochondrial biogenesis, mitophagy, mitochondrial dynamics, mitochondrial oxidative phosphorylation, and oxidative stress, dysfunctions of all of the above processes are associated with podocyte damage in DKD ( Liu et al, 2022 ). Evidence showed that mitochondrial dysfunction contributes to the development and progression of fibrosis, including renal fibrosis ( Li et al, 2020 ).…”

SIRT1–SIRT7 in Diabetic Kidney Disease: Biological Functions and Molecular Mechanisms

“…DKD is a microvascular complication of DM that develops from micro-proteinuria to massive proteinuria, ultimately leading to end-stage renal disease (18). Importantly, metabolic and hemodynamic changes in DM cause ultrastructural changes in the glomerular filtration barrier, including podocyte foot process fusion and separation, GBM thickening, reduction of endothelial cell glycocalyx, accumulation of mesangial extracellular matrix, and glomerular sclerosis, all of which are directly related to the increase in proteinuria (20).…”