Dicarbonyl-modified lipoproteins contribute to proteinuric kidney injury

Zhong, Jian; Yang, Haichun; Shelton, Elaine L.; Matsusaka, Taiji; Clark, Amanda J.; Yermalitsky, Valery; Mashhadi, Zahra; May-Zhang, Linda S.; Linton, MacRae F.; Fogo, Agnes B.; Kirabo, Annet; Davies, Sean S.; Kon, Valentina

doi:10.1172/jci.insight.161878

Cited by 3 publications

(3 citation statements)

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“…232 The compounds effectively scavenge reactive dicarbonyls including IsoLG, ONE, and MDA and to a lesser extent some monocarbonyls like ACR. They have shown remarkable efficacy in a number of animal models of oxidative damage including Alzheimer disease, 233 hypertension, 232,234,235 proteinuric kidney disease, 201 lupus, 236 cardiac ischemia/reperfusion injury, 237 and gastric cancer. 238…”

Section: Small Molecule Scavengers Of Lipid Dicarbonyls As Inhibitors...mentioning

confidence: 99%

“…32,200 Urinary apoAI from individuals with CKD shows higher levels of IsoLG modification. 201 Another challenge to understanding the actual extent of HDL modification in vivo and whether this correlates with disease progression is that modification of HDL proteins such as apoAI appears to primarily occur outside the plasma compartment. This conclusion is based on the findings that levels of apoAI modification are significantly greater for apoAI/HDL isolated from atherosclerotic lesions compared with that isolated from circulation.…”

Section: Oxidative Modification Of Hdl Proteins In Vivomentioning

confidence: 99%

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HDL Function and Atherosclerosis: Reactive Dicarbonyls as Promising Targets of Therapy

Linton

Yancey

Huan

et al. 2023

Circulation Research

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Epidemiologic studies detected an inverse relationship between HDL (high-density lipoprotein) cholesterol (HDL-C) levels and atherosclerotic cardiovascular disease (ASCVD), identifying HDL-C as a major risk factor for ASCVD and suggesting atheroprotective functions of HDL. However, the role of HDL-C as a mediator of risk for ASCVD has been called into question by the failure of HDL-C–raising drugs to reduce cardiovascular events in clinical trials. Progress in understanding the heterogeneous nature of HDL particles in terms of their protein, lipid, and small RNA composition has contributed to the realization that HDL-C levels do not necessarily reflect HDL function. The most examined atheroprotective function of HDL is reverse cholesterol transport, whereby HDL removes cholesterol from plaque macrophage foam cells and delivers it to the liver for processing and excretion into bile. Indeed, in several studies, HDL has shown inverse associations between HDL cholesterol efflux capacity and ASCVD in humans. Inflammation plays a key role in the pathogenesis of atherosclerosis and vulnerable plaque formation, and a fundamental function of HDL is suppression of inflammatory signaling in macrophages and other cells. Oxidation is also a critical process to ASCVD in promoting atherogenic oxidative modifications of LDL (low-density lipoprotein) and cellular inflammation. HDL and its proteins including apoAI (apolipoprotein AI) and PON1 (paraoxonase 1) prevent cellular oxidative stress and LDL modifications. Importantly, HDL in humans with ASCVD is oxidatively modified rendering HDL dysfunctional and proinflammatory. Modification of HDL with reactive carbonyl species, such as malondialdehyde and isolevuglandins, dramatically impairs the antiatherogenic functions of HDL. Importantly, treatment of murine models of atherosclerosis with scavengers of reactive dicarbonyls improves HDL function and reduces systemic inflammation, atherosclerosis development, and features of plaque instability. Here, we discuss the HDL antiatherogenic functions in relation to oxidative modifications and the potential of reactive dicarbonyl scavengers as a therapeutic approach for ASCVD.

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Section: Small Molecule Scavengers Of Lipid Dicarbonyls As Inhibitors...mentioning

confidence: 99%

Section: Oxidative Modification Of Hdl Proteins In Vivomentioning

confidence: 99%

HDL Function and Atherosclerosis: Reactive Dicarbonyls as Promising Targets of Therapy

Linton

Yancey

Huan

et al. 2023

Circulation Research

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“…Critically, treatment to scavenge IsoLGs significantly reduced intestinal lymphangiogenesis, albuminuria, and interstitial fibrosis supporting the concept that intestinal lymphatic growth associated with kidney injury is linked to IsoLG. 3,131 Thus, the mesenteric lymphatic network appears to serve as both target and perpetrator of IsoLG-HDL’s effects by augmenting lymphangiogenesis, lymphatic vessel contractions, LEC activation, and increased lymph flow.…”

Section: Mechanisms By Which Kidney Disease Can Modify the Lymphatic ...mentioning

confidence: 99%

Intestinal Lymphatic Dysfunction in Kidney Disease

Zhong

Kirabo

Yang

et al. 2023

Circulation Research

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Kidney disease is associated with adverse consequences in many organs beyond the kidney, including the heart, lungs, brain, and intestines. The kidney-intestinal cross talk involves intestinal epithelial damage, dysbiosis, and generation of uremic toxins. Recent studies reveal that kidney injury expands the intestinal lymphatics, increases lymphatic flow, and alters the composition of mesenteric lymph. The intestinal lymphatics, like blood vessels, are a route for transporting potentially harmful substances generated by the intestines. The lymphatic architecture and actions are uniquely suited to take up and transport large macromolecules, functions that differentiate them from blood vessels, allowing them to play a distinct role in a variety of physiological and pathological processes. Here, we focus on the mechanisms by which kidney diseases result in deleterious changes in intestinal lymphatics and consider a novel paradigm of a vicious cycle of detrimental organ cross talk. This concept involves kidney injury–induced modulation of intestinal lymphatics that promotes production and distribution of harmful factors, which in turn contributes to disease progression in distant organ systems.

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Inflammation Biomarker Response to Oral 2-Hydroxybenzylamine (2-HOBA) Acetate in Healthy Humans

et al. 2023

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Inflammation is associated with the formation of reactive oxygen species (ROS) and the formation of lipid-derived compounds, such as isolevuglandins (IsoLGs), malondialdehyde, 4-hydroxy-nonenal, and 4-oxo-nonenal. The most reactive of these are the IsoLGs, which form covalent adducts with lysine residues and other cellular primary amines leading to changes in protein function, immunogenicity, and epigenetic alterations and have been shown to contribute to a number of inflammatory diseases. 2-Hydroxybenzylamine (2-HOBA) is a natural compound found in buckwheat seeds and reacts with all IsoLG adducts preventing adduct formation with proteins and DNA. Therefore, 2-HOBA is well positioned as an agent for the prevention of inflammatory-prone diseases. In this study, we examined the potential beneficial effects of 2-HOBA on oxidative stress and inflammatory biomarkers in two cohorts of healthy younger and older adults. We utilized the Olink ® targeted inflammation panel before and after an oral 15-day treatment regimen with 2-HOBA. We found significant relative changes in the plasma concentration of 15 immune proteins that may reflect the in vivo immune targets of 2-HOBA. Treatment of 2-HOBA resulted in significant increased levels of CCL19, IL-12β, IL-20Rα, and TNFβ, whereas levels of TWEAK significantly decreased. Ingenuity Pathway Analysis identified canonical pathways regulated by the differentially secreted cytokines, chemokines, and growth factors upon 2-HOBA treatment and further points to biofunctions related to the recruitment, attraction, and movement of different immune cell types. In conclusion, 2-HOBA significantly altered the protein biomarkers CCL19, IL-12β, IL-20Rα, TNFβ, and TWEAK, and these may be responsible for the protective effects of 2-HOBA against reactive electrophiles, such as IsoLGs, commonly expressed in conditions of excessive oxidative stress. 2-HOBA has a role as a IsoLG scavenger to proactively improve immune health in a variety of conditions. Supplementary Information The online version contains supplementary material available at 10.1007/s10753-023-01801-w.

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Dicarbonyl-modified lipoproteins contribute to proteinuric kidney injury

Cited by 3 publications

References 50 publications

HDL Function and Atherosclerosis: Reactive Dicarbonyls as Promising Targets of Therapy

HDL Function and Atherosclerosis: Reactive Dicarbonyls as Promising Targets of Therapy

Intestinal Lymphatic Dysfunction in Kidney Disease

Inflammation Biomarker Response to Oral 2-Hydroxybenzylamine (2-HOBA) Acetate in Healthy Humans

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