Oxidative Stress Induced by Lipotoxicity and Renal Hypoxia in Diabetic Kidney Disease and Possible Therapeutic Interventions: Targeting the Lipid Metabolism and Hypoxia

Abstract

Oxidative stress, a hallmark pathophysiological feature in diabetic kidney disease (DKD), arises from the intricate interplay between pro-oxidants and anti-oxidants. While hyperglycemia has been well established as a key contributor, lipotoxicity emerges as a significant instigator of oxidative stress. Lipotoxicity encompasses the accumulation of lipid intermediates, culminating in cellular dysfunction and cell death. However, the mechanisms underlying lipotoxic kidney injury in DKD still require further investigation. The key role of cell metabolism in the maintenance of cell viability and integrity in the kidney is of paramount importance to maintain proper renal function. Recently, dysfunction in energy metabolism, resulting from an imbalance in oxygen levels in the diabetic condition, may be the primary pathophysiologic pathway driving DKD. Therefore, we aim to shed light on the pivotal role of oxidative stress related to lipotoxicity and renal hypoxia in the initiation and progression of DKD. Multifaceted mechanisms underlying lipotoxicity, including oxidative stress with mitochondrial dysfunction, endoplasmic reticulum stress activated by the unfolded protein response pathway, pro-inflammation, and impaired autophagy, are delineated here. Also, we explore potential therapeutic interventions for DKD, targeting lipotoxicity- and hypoxia-induced oxidative stress. These interventions focus on ameliorating the molecular pathways of lipid accumulation within the kidney and enhancing renal metabolism in the face of lipid overload or ameliorating subsequent oxidative stress. This review highlights the significance of lipotoxicity, renal hypoxia-induced oxidative stress, and its potential for therapeutic intervention in DKD.

Linking MDA Levels and Blood Glucose in Streptozotocin-Induced Rat Diabetes: Implications for Diabetic Complications and Therapeutic Strategies

“…MDA is a reactive aldehyde formed as a byproduct of lipid peroxidation, a process that occurs when free radicals attack polyunsaturated fatty acids in cell membranes. Measurement of MDA levels provides valuable insights into the extent of oxidative stress and the efficacy of antioxidant interventions in mitigating cellular damage (Park et al, 2023;Olufunmilayo et al, 2023;Chaudhary et al, 2023).…”

“…MDA, a reactive aldehyde compound formed during lipid peroxidation, stands as a reliable biomarker for oxidative stress (Sidorova & Domanskyi, 2020). When STZ-induced diabetes disrupts the delicate balance between pro-oxidants and antioxidants, it leads to heightened oxidative stress, exacerbating tissue damage and dysfunction (Arabshomali et al, 2023;Chae et al, 2023). By examining MDA levels alongside blood glucose concentrations, researchers gain a comprehensive understanding of the interplay between hyperglycemia-induced oxidative stress and diabetic pathogenesis, which could pave the way for novel therapeutic strategies targeting oxidative stress pathways alongside traditional glycemic control measures to mitigate diabetic complications and improve overall disease management.…”

The ameliorative mechanism of Lactiplantibacillus plantarum NJAU-01 against d-galactose induced oxidative stress: a hepatic proteomics and gut microbiota analysis

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Overnutrition and Lipotoxicity: Impaired Efferocytosis and Chronic Inflammation as Precursors to Multifaceted Disease Pathogenesis

“…While ROS serve important roles in cell signaling, they can also lead to oxidative stress when produced in excess or when the cellular antioxidant defense mechanisms are overwhelmed [92]. In the domain of lipotoxicity, excessive lipid buildup in tissues beyond the adipose tissues can initiate mitochondrial dysfunction, inflammation, and oxidative stress, leading to an escalation in reactive oxygen species (ROS) generation [93].…”

“…Lipotoxicity often leads to mitochondrial dysfunction, which is characterized by impaired electron transport chain (ETC) activity, reduced ATP production, and increased electron leakage, resulting in elevated ROS generation within the mitochondria [93,94]. Excessive ROS production overwhelms the cellular antioxidant defense systems, including enzymes like superoxide dismutase (SOD), catalase, and glutathione peroxidase, as well as non-enzymatic antioxidants such as glutathione and vitamins C and E [95].…”