Genetic susceptibility to diabetic kidney disease is linked to promoter variants of XOR

Wang, Qin; Qi, Haiying; Wu, Yiming; Yu, Liping; Bouchareb, Rihab; Li, Shuyu; Lassén, Emelie; Casalena, Gabriella; Stadler, Krisztián; Ebefors, Kerstin; Yi, Zhengzi; Shi, Shaolin; Salem, Fadi; Gordon, Ronald E.; Lu, Lu; Williams, Robert W.; Duffield, Jeremy S.; Zhang, Weijia; Itan, Yuval; Böttinger, Erwin; Daehn, Ilse

doi:10.1038/s42255-023-00776-0

Cited by 7 publications

(11 citation statements)

References 105 publications

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“…Increased XOR in streptozotocin-induced DKD was associated with increased VEGF/VEGF receptor 1 and VEGF receptor 3 levels in the kidneys, followed by the activation of NOX1, NOX2, and NOX4 expression and by FoxO3a phosphorylation and activation of eNOS. In our study, we demonstrated that XOR inhibition prevented mitochondrial oxidative DNA damage ( 110 ); hence, a potential feedforward interplay between XOR-derived ROS enhancing mitochondria-derived ROS release could provide a mechanism that promotes a vicious cycle of sustained stress and accumulation of oxidized products. Understanding these interactions is important, as they are derived through various sources of ROS in DKD; hence, studies assessing the contribution of redox processes in DKD are expected to provide valuable tools in DKD therapy in the upcoming years.…”

Section: Sources Of Reactive Species: Cellular Mitochondrial and Enzy...mentioning

confidence: 78%

“…The biggest advantage is, as it is spectroscopy, the unambiguous identification of the paramagnetic species, the radical adduct itself instead of fingerprint products or secondary species derived from the free radical reaction. We and others have demonstrated the applicability of the technique in renal cells and kidney tissue, from NO detection to lipid peroxidation ( 64 , 110 , 120 , 154 , 180 ). The disadvantages are that not everyone has access to EPR, nor it has become widespread in biology research as it requires specific training in biophysics.…”

Section: Measuring Reactive Species In Dkdmentioning

confidence: 98%

“…We have recently demonstrated that DKD predisposition in mice was attributed to a variant regulating XOR activity and a higher redox state in diabetes ( 110 ). We also uncovered promoter XOR ortholog variants in humans associated with a high risk for DKD and other diabetic complications.…”

Section: Sources Of Reactive Species: Cellular Mitochondrial and Enzy...mentioning

confidence: 99%

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Redox regulation in diabetic kidney disease

Daehn

Ekperikpe

Stadler

2023

American Journal of Physiology-Renal Physiology

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Diabetic kidney disease (DKD) is one of the most devastating complications of diabetes mellitus, where currently there is no cure available. Several important mechanisms contribute to the pathogenesis of this complication, with oxidative stress being one of the key factors. The past decades have seen a large number of publications with various aspects of this topic, however, the specific details of redox regulation in DKD are still unclear. Partially this is because redox biology is very complex, coupled with a complex and heterogeneous organ with numerous cell types. Furthermore, often times terms such as "oxidative stress" or reactive oxygen species (ROS) are used as a general term to cover a wide and rich variety of reactive species and their differing reactions. However, no reactive species are the same and not all of them are capable of biologically relevant reactions or "redox signaling". The goal of this review is to provide a biochemical background for an array of specific ROS types with varying reactivity and specificity in the kidney, as well as highlight some of the advances in redox biology that are paving the way to a better understanding DKD development and risk.

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Section: Sources Of Reactive Species: Cellular Mitochondrial and Enzy...mentioning

confidence: 78%

Section: Measuring Reactive Species In Dkdmentioning

confidence: 98%

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Redox regulation in diabetic kidney disease

Daehn

Ekperikpe

Stadler

2023

American Journal of Physiology-Renal Physiology

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“…However, it is known that diabetes mellitus has the disorder of glucose and lipid metabolism, and oxidative stress also plays an important role in diabetic glomerular cell injury, and the degree of podocyte depletion correlates with disease severity [ 59 ]. Recent studies have found that Glomerular endothelial cell (GEC) dysfunction has been attributed to the pathogenesis of DKD [ 60 , 61 ]. Inhibiting mitochondrial oxidative stress with drugs can delay the progression of DKD by improving the damage of GEC [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial oxidative damage reprograms lipid metabolism of renal tubular epithelial cells in the diabetic kidney

Hou,

Tan,

Shi

et al. 2024

Cell. Mol. Life Sci.

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The functional and structural changes in the proximal tubule play an important role in the occurrence and development of diabetic kidney disease (DKD). Diabetes-induced metabolic changes, including lipid metabolism reprogramming, are reported to lead to changes in the state of tubular epithelial cells (TECs), and among all the disturbances in metabolism, mitochondria serve as central regulators. Mitochondrial dysfunction, accompanied by increased production of mitochondrial reactive oxygen species (mtROS), is considered one of the primary factors causing diabetic tubular injury. Most studies have discussed how altered metabolic flux drives mitochondrial oxidative stress during DKD. In the present study, we focused on targeting mitochondrial damage as an upstream factor in metabolic abnormalities under diabetic conditions in TECs. Using SS31, a tetrapeptide that protects the mitochondrial cristae structure, we demonstrated that mitochondrial oxidative damage contributes to TEC injury and lipid peroxidation caused by lipid accumulation. Mitochondria protected using SS31 significantly reversed the decreased expression of key enzymes and regulators of fatty acid oxidation (FAO), but had no obvious effect on major glucose metabolic rate-limiting enzymes. Mitochondrial oxidative stress facilitated renal Sphingosine-1-phosphate (S1P) deposition and SS31 limited the elevated Acer1, S1pr1 and SPHK1 activity, and the decreased Spns2 expression. These data suggest a role of mitochondrial oxidative damage in unbalanced lipid metabolism, including lipid droplet (LD) formulation, lipid peroxidation, and impaired FAO and sphingolipid homeostasis in DKD. An in vitro study demonstrated that high glucose drove elevated expression of cytosolic phospholipase A2 (cPLA2), which, in turn, was responsible for the altered lipid metabolism, including LD generation and S1P accumulation, in HK-2 cells. A mitochondria-targeted antioxidant inhibited the activation of cPLA2f isoforms. Taken together, these findings identify mechanistic links between mitochondrial oxidative metabolism and reprogrammed lipid metabolism in diabetic TECs, and provide further evidence for the nephroprotective effects of SS31 via influencing metabolic pathways.

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“…XOR activity can be influenced by environmental factors, such as purine-rich and Western diets, infections, and increasing temperatures. Various disease states such as diabetes and aging can also enhance XOR activity [ 4 , 5 ]. Consequently, hyperuricemia (defined as elevated levels of serum UA) together with the generation of excess ROS can elicit damage to tissues, particularly on the endothelium [ 6 , 7 , 8 , 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Emerging Roles of Xanthine Oxidoreductase in Chronic Kidney Disease

Korsmo,

Ekperikpe,

Daehn

2024

Antioxidants

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Xanthine Oxidoreductase (XOR) is a ubiquitous, essential enzyme responsible for the terminal steps of purine catabolism, ultimately producing uric acid that is eliminated by the kidneys. XOR is also a physiological source of superoxide ion, hydrogen peroxide, and nitric oxide, which can function as second messengers in the activation of various physiological pathways, as well as contribute to the development and the progression of chronic conditions including kidney diseases, which are increasing in prevalence worldwide. XOR activity can promote oxidative distress, endothelial dysfunction, and inflammation through the biological effects of reactive oxygen species; nitric oxide and uric acid are the major products of XOR activity. However, the complex relationship of these reactions in disease settings has long been debated, and the environmental influences and genetics remain largely unknown. In this review, we give an overview of the biochemistry, biology, environmental, and current clinical impact of XOR in the kidney. Finally, we highlight recent genetic studies linking XOR and risk for kidney disease, igniting enthusiasm for future biomarker development and novel therapeutic approaches targeting XOR.

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Genetic susceptibility to diabetic kidney disease is linked to promoter variants of XOR

Cited by 7 publications

References 105 publications

Redox regulation in diabetic kidney disease

Redox regulation in diabetic kidney disease

Mitochondrial oxidative damage reprograms lipid metabolism of renal tubular epithelial cells in the diabetic kidney

Emerging Roles of Xanthine Oxidoreductase in Chronic Kidney Disease

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