It Takes Two to Tango: The Role of Dysregulated Metabolism and Inflammation in Kidney Disease Development

Quinn, Ghazal; Dhillon, Poonam; Suszták, Katalin

doi:10.1016/j.semnephrol.2020.01.010

Cited by 11 publications

(8 citation statements)

References 53 publications

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“…The importance of these cells in the pathophysiological process of AKI and CKD is now well-established and the specific influence of PTC metabolic alterations in the pathological processes of renal disease has received increasing attention. Among metabolic alterations, mitochondrial dysfunction (21)(22)(23)(24)(25)(26)(27) and FAO downregulation (21, 28-30) have been described and already been reviewed (31)(32)(33)(34)(35)(36). We here describe in more details the modifications of glucose metabolism in PTCs that occurs during acute and chronic injuries.…”

Section: Glucose Metabolism During Kidney Diseasementioning

confidence: 91%

“…Initially, the switch constitutes a protective mechanism allowing PTCs to maintain energy production in case of low oxygen supply: HIF activation indeed enhances glycolysis through the stimulation of several enzymes of the pathway (hexokinases, glyceraldehyde-3phosphate dehydrogenase, enolases, phosphofructokinases) and through the activation of glucose transporters (GLUT1-3) (75)(76)(77). In later stages of renal disease, inflammation and TGFβ activation could also play an important role in the persistence of the metabolic switch (78,79); the induction of glycolysis was reproduced by IL-β and c-myc signaling activation (32,52). In addition, the expression of co-regulators of FAO and glycolysis such as HNF4α or estrogen-related receptor alpha (ESRRA) are modified during AKI (74).…”

Section: Glucose Metabolism During Kidney Diseasementioning

confidence: 99%

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Tubular Cell Glucose Metabolism Shift During Acute and Chronic Injuries

et al. 2021

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Acute and chronic kidney disease are responsible for large healthcare costs worldwide. During injury, kidney metabolism undergoes profound modifications in order to adapt to oxygen and nutrient shortage. Several studies highlighted recently the importance of these metabolic adaptations in acute as well as in chronic phases of renal disease, with a potential deleterious effect on fibrosis progression. Until recently, glucose metabolism in the kidney has been poorly studied, even though the kidney has the capacity to use and produce glucose, depending on the segment of the nephron. During physiology, renal proximal tubular cells use the beta-oxidation of fatty acid to generate large amounts of energy, and can also produce glucose through gluconeogenesis. In acute kidney injury, proximal tubular cells metabolism undergo a metabolic shift, shifting away from beta-oxidation of fatty acids and gluconeogenesis toward glycolysis. In chronic kidney disease, the loss of fatty acid oxidation is also well-described, and data about glucose metabolism are emerging. We here review the modifications of proximal tubular cells glucose metabolism during acute and chronic kidney disease and their potential consequences, as well as the potential therapeutic implications.

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Section: Glucose Metabolism During Kidney Diseasementioning

confidence: 91%

Section: Glucose Metabolism During Kidney Diseasementioning

confidence: 99%

Tubular Cell Glucose Metabolism Shift During Acute and Chronic Injuries

et al. 2021

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“…16 Constitutive cGAS-STING pathway activation and associated effector functions, such as interferon production, can result in cell or tissue damage. Consistent with this notion, dysregulation of the cGAS-STING signaling pathway in adipocytes, 17 hepatocytes, 18 and renal tubule cells [19][20][21] are associated with metabolic dysfunction, impaired energy homeostasis, and kidney diseases. Beyond the canonical role of cGAS-STING in mediating cytokine production, growing evidence highlights the emerging role in regulating autophagy and cell death (e.g., apoptosis, necroptosis, pyroptosis, ferroptosis, mitotic cell death, and immunogenic cell death).…”

Section: Introductionmentioning

confidence: 62%

Activation of cGAS‐STING pathway – A possible cause of myofiber atrophy/necrosis in dermatomyositis and immune‐mediated necrotizing myopathy

Zhou

Cheng

Zhu

et al. 2022

Clinical Laboratory Analysis

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Objective:The objective was to investigate the expression of the cGAS-STING pathway-associated protein in idiopathic inflammatory myopathy (IIM) and to investigate whether it is related to myofiber atrophy/necrosis in patients with dermatomyositis and immune-mediated necrotizing myopathy. Material and Methods: Muscle specimens obtained by open biopsy from 26 IIM patients (14 with dermatomyositis (DM), 8 with immune-mediated necrotizing myopathy (IMNM), and 4 with other types of IIM), 4 dystrophinopathy, and 9 control patients were assessed for expression of cGAS-STING pathway members via Western blot, quantitative real-time PCR analysis (qRT-PCR), and immunochemistry. Meanwhile, analysis its location distribution througn immunochemistry.Results: Compared to the control group, the expression of cGAS, STING, and related molecules was obviously increased in muscle samples of IIM patients. Upregulated cGAS and STING were mainly located in the vascular structure, inflammatory infiltrates, and atrophic and necrotic fibers. While comparing to the Dys patients, the mRNA level of cGAS, STING, and TNF-a was upregulated, meanwhile, the protein of the TBK1, P-TBK1, and P-IRF3 associated with interferon upregulation was overexpressed through Western blot in IMNM and DM. Considering that cGAS and STING are located in necrotic and Mx1-positive atrophic fibers, it is really possible that the cGAS-STING pathway may lead to fibers atrophy/necrosis by producing IFNs. Conclusion:The cGAS-STING pathway was activated in the muscle samples of IIM patients and its activation may be the reason of myofiber atrophy and necrosis in DM and IMNM patients.

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“…Since NETs represented the target parameter of the primary study, these conditions might have biased the study results, and were therefore matched in the control and septic shock group. Since these conditions are also connected to an impaired mitochondrial function, the matching strategy is also appropriate for this secondary analysis [ 21 , 22 , 23 , 24 ]. Visceral surgical patients underwent major abdominal surgery (MAS), such as Whipple’s procedure, oncological gastric or esophageal resection, or colectomy, whereas all cardiac surgical patients received coronary artery bypass graft (CABG) surgery.…”

Section: Methodsmentioning

confidence: 99%

Blood Levels of Free-Circulating Mitochondrial DNA in Septic Shock and Postsurgical Systemic Inflammation and Its Influence on Coagulation: A Secondary Analysis of a Prospective Observational Study

Schneck

Edinger

Hecker

et al. 2020

JCM

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Major surgery is regularly associated with clinical signs of systemic inflammation, which potentially affects the rapid identification of sepsis. Therefore, this secondary analysis of an observational study aims to determine whether NADH dehydrogenase 1 (ND1) mitochondrial DNA (mtDNA) could be used as a potential biomarker for the discrimination between septic shock and postsurgical systemic inflammation. Overall, 80 patients were included (septic shock (n = 20), cardiac artery bypass grafting (CABG, n = 20), major abdominal surgery (MAS, n = 20), and matched controls (CTRL, n = 20)). Quantitative PCR was performed to measure ND1 mtDNA. Thromboelastography was used to analyze the coagulatory system. Free-circulating ND1 mtDNA levels were significantly higher in septic shock patients compared to patients suffering from post-surgical inflammation ({copies/µL}: CTRL: 1208 (668–2685); septic shock: 3823 (2170–7318); CABG: 1272 (417–2720); and MAS: 1356 (694–2845); CTRL vs. septic shock: p < 0.001; septic shock vs. CABG: p < 0.001; septic shock vs. MAS: p = 0.006; CABG vs. MAS: p = 0.01). ND1 mtDNA levels in CABG patients showed a strong positive correlation with fibrinogen (correlation coefficient [r]= 0.57, p < 0.001) and fibrinogen-dependent thromboelastographic assays (maximum clot firmness, EXTEM: r = 0.35, p = 0.01; INTEM: r = 0.31, p = 0.02; FIBTEM: r = 0.46, p < 0.001). In conclusion, plasma levels of free-circulating ND1 mtDNA were increased in septic shock patients and were discriminative between sepsis and surgery-induced inflammation. Furthermore, this study showed an association between ND1 mtDNA and a fibrinogen-dependent pro-coagulatory shift in cardiac surgical patients.

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It Takes Two to Tango: The Role of Dysregulated Metabolism and Inflammation in Kidney Disease Development

Cited by 11 publications

References 53 publications

Tubular Cell Glucose Metabolism Shift During Acute and Chronic Injuries

Tubular Cell Glucose Metabolism Shift During Acute and Chronic Injuries

Activation of cGAS‐STING pathway – A possible cause of myofiber atrophy/necrosis in dermatomyositis and immune‐mediated necrotizing myopathy

Blood Levels of Free-Circulating Mitochondrial DNA in Septic Shock and Postsurgical Systemic Inflammation and Its Influence on Coagulation: A Secondary Analysis of a Prospective Observational Study

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