Obesity and Diabetic Kidney Disease: Role of Oxidant Stress and Redox Balance

Abstract

Significance: Reactive oxygen species (ROS) reactive nitrogen species (RNS) and redox processes are of key importance in obesity-and diabetes-related kidney disease; however, there remains significant controversy in the field. Recent Advances: New data from imaging and in vivo models of obesity and diabetic kidney disease have shed new insights into this field. In the setting of obesity-and diabetes-related kidney injury, there is a growing recognition that the major moieties of ROS and RNS are hydrogen peroxide and peroxynitrite with the enzymatic sources being NADPH oxidases and nitric oxide synthase, respectively. However, the role of mitochondrial superoxide as a driver of renal complications remains unclear. Critical Issues: Several key issues that are often not discussed are the specific ROS and RNS molecules, the source of generation, the location of production, and downstream targets. Future Directions: Further understanding of the role of ROS/RNS/redox and their relationship with key signaling and metabolic pathways such as AMP-activated protein kinase (AMPK) and hypoxia-inducible factor 1-a (HIF1a) will be critical to a new understanding of kidney complications of caloric challenges and new therapeutic approaches. Antioxid. Redox Signal. 25,[208][209][210][211][212][213][214][215][216]

The Warburg Effect in Diabetic Kidney Disease

“…8,49 The major sources of endogenous ROS in the diabetic kidney include mitochondria, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, nitric oxide synthases, xanthine oxidase, and lipoxygenase. 8,49,50 ROS include the free radical superoxide anion $false({\mathrm{O}}_2^{.-}false)$, the nonradical hydrogen peroxide (H 2 O 2 ), highly reactive hydroxyl free radical (.OH), peroxynitrite (ONOO − ), and singlet oxygen ( 1 O 2 ). Specifically, ${\mathrm{O}}_2^{-}$, H 2 O 2 , and ONOO − have been investigated mostly in the diabetic kidney.…”

“…52–54 In particular, a common belief is that mitochondrial superoxide is a major contributor for diabetic complications, such as DKD. 49,55,56 However, anti-oxidant–based clinical trials have proven to be largely negative. 57 Based on the new evidence, the theory of "mitochondrial hormesis" has been proposed wherein optimal levels of ROS are considered a marker for functional mitochondria.…”

“…49 HIF-1α and HIF-2α are transcription factors that up-regulate aerobic glycolysis-associated genes (eg, glucose transporter and vascular endothelial growth factor) in cancer. Both glucose transporter and vascular endothelial growth factor enhance glucose transport and tumor vascularity.…”

“…69,70 Results from MSI, gene expression, protein, and metabolomic analyses suggest a potential feedback loop mechanism (ie, increased ATP/AMP, reduced AMPK, activated NOX4, increased H 2 O 2 , suppressed FH, accumulated fumarate, increased HIF-1α, and enhanced glycolysis) in the development of DKD. 49 More sophisticated approaches are needed to accurately determine the sources of ATP and ROS that can provide further insights into the pathogenesis of DKD.…”

“…Omics-based systems biology, which incorporate different tiers of biological data, has shed new insights into our understanding of DKD and has provided several key breakthroughs for novel predictive and diagnostic biomarkers. Recent omics-based investigations coupled with systems biology tools have shown that mitochondrial dysfunction, 20 oxidative stress (eg, ROS), 49 alterations of multitier information (eg, genes, proteins, and metabolites), and major metabolic pathways (eg, the TCA cycle, glycolysis, fatty acid metabolism, and amino acid metabolism) 16,21,22 all are altered in a manner consistent with a Warburg-type effect in diabetic nephropathy.…”