Metabolic reprogramming: A novel therapeutic target in diabetic kidney disease

Abstract

Diabetic kidney disease (DKD) is one of the most common microvascular complications of diabetes mellitus. However, the pathological mechanisms contributing to DKD are multifactorial and poorly understood. Diabetes is characterized by metabolic disorders that can bring about a series of changes in energy metabolism. As the most energy-consuming organs secondary only to the heart, the kidneys must maintain energy homeostasis. Aberrations in energy metabolism can lead to cellular dysfunction or even death. Metabolic reprogramming, a shift from mitochondrial oxidative phosphorylation to glycolysis and its side branches, is thought to play a critical role in the development and progression of DKD. This review focuses on the current knowledge about metabolic reprogramming and the role it plays in DKD development. The underlying etiologies, pathological damages in the involved cells, and potential molecular regulators of metabolic alterations are also discussed. Understanding the role of metabolic reprogramming in DKD may provide novel therapeutic approaches to delay its progression to end-stage renal disease.

Inhibition of PFKP in renal tubular epithelial cell restrains TGF-β induced glycolysis and renal fibrosis

“…The energy requirements of these cells are primarily satisfied by ATP generated via oxidative phosphorylation (OXPHOS), and FAO contributes about 70% of the total supply. However, in the case of diabetes, cell metabolism changes from FAO to glycolysis or its side branches in PETCs [ 11 ]. Indeed, treatment of mice with the glycolysis inhibitor 2-DG ameliorated PTECs proliferation, cystogenesis, and kidney fibrosis [ 37 ].…”

“…After kidney injury, the FAO ability of PTECs is impaired, leading to metabolic reprogramming of cells to provide energy [ 10 ]. Metabolic reprogramming, a shift from mitochondrial FAO to glycolysis in PETCs, is considered to play an important role in CKD progression [ 11 ]. In the case of diabetes, due to changes in metabolic substrates and oxygen delivery, renal tubules suffer from hypoxia, glycolysis, and lipid accumulation, resulting in increased production of reactive oxygen species (ROS), proinflammatory and profibrotic factors, and increased PTECs apoptosis and renal fibrosis [ 11 , 12 ].…”

Recent progress in metabolic reprogramming in gestational diabetes mellitus: a review

“…Mitochondrial dysfunction results from impaired cellular respiration or defects in mitochondrial quality control, mainly reflected in the OXPHOS machinery ( 20 ). Metabolic reprogramming is involved in many diseases, including cancer, diabetes, and rare genetic diseases, mainly through mitochondrial OXPHOS ( 15 , 21 , 22 ). Mitochondrial OXPHOS comprises ATP synthase and the electron transport chain.…”

“…A balanced metabolic system is essential for the structural stability of glucose and normal physiological function. Metabolic processes can adapt to changes in the environment; thus, they can be reprogrammed to support energy requirements in biosynthesis, leading to disease development such as cancer, diabetes, polycystic kidney disease, and vascular inflammatory diseases (15)(16)(17)(18). Metabolic reprogramming is also important in GDM development (11)(12)(13).…”

Biochemical Profiles of Different Approaches Applied to Induction of Diabetes in Rats

“…The original and public diagnostic guides of DM are hyperglycemia and (in severe cases) glycosuria. In that concern, the irregular metabolism of carbohydrates in DM, and related thoughtful modifications of glycolytic pathways [5,6] provoke the stimulation of substitute polyol metabolic pathways with a subsequent intracellular gathering of sorbitol [7] and glucose auto-oxidation [8]. These unbalanced metabolic events have been concerned in the pathogenesis of diabetic peripheral retinopathy, and neuropathy, as well as, in the fluctuations in the body weight, and body mass index [9,10].…”