Immunometabolic rewiring of tubular epithelial cells in kidney disease

Rijt, Sanne van der; Leemans, Jaklien C.; Florquin, Sandrine; Houtkooper, Riekelt H.; Tammaro, Alessandra

doi:10.1038/s41581-022-00592-x

Cited by 46 publications

(26 citation statements)

References 166 publications

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“…Proximal tubular epithelial cells rely on their energy demand by using fatty acid oxidation rather than glycolysis, and glucose in the proximal tubular epithelial cell is shunted into the pentose phosphate pathway that can maintain antioxidant glutathione in its reduced state in response to injury 31 . Enhanced oxidative stress, along with increased metabolites of the tricyclic acid cycle upon high-glucose stimulation, resulted in altered glutathione metabolism in diabetic kidney tissue 32 .…”

Section: Discussionmentioning

confidence: 99%

Metabolomic profiling in kidney cells treated with a sodium glucose-cotransporter 2 inhibitor

Seo

Lee

et al. 2023

Sci Rep

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We aimed to determine the metabolomic profile of kidney cells under high glucose conditions and following sodium-glucose cotransporter 2 (SGLT2) inhibitor treatment. Targeted metabolomics using the Absolute IDQ-p180 kit was applied to quantify metabolites in kidney cells stimulated with high glucose (25 and 50 mM) and treated with SGLT2 inhibitor, dapagliflozin (2 µM). Primary cultured human tubular epithelial cells and podocytes were used to identify the metabolomic profile in high glucose conditions following dapagliflozin treatment. The levels of asparagine, PC ae C34:1, and PC ae C36:2 were elevated in tubular epithelial cells stimulated with 50 mM glucose and were significantly decreased after 2 µM dapagliflozin treatment. The level of PC aa C32:0 was significantly decreased after 50 mM glucose treatment compared with the control, and its level was significantly increased after dapagliflozin treatment in podocytes. The metabolism of glutathione, asparagine and proline was significantly changed in tubular epithelial cells under high-glucose stimulation. And the pathway analysis showed that aminoacyl-tRNA biosynthesis, arginine and proline metabolism, glutathione metabolism, valine, leucine and isoleucine biosynthesis, phenylalanine, tyrosine, and tryptophan biosynthesis, beta-alanine metabolism, phenylalanine metabolism, arginine biosynthesis, alanine, aspartate and glutamate metabolism, glycine, serine and threonine metabolism were altered in tubular epithelial cells after dapagliflozin treatment following 50 mM glucose compared to those treated with 50 mM glucose.

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Section: Discussionmentioning

confidence: 99%

Metabolomic profiling in kidney cells treated with a sodium glucose-cotransporter 2 inhibitor

Seo

Lee

et al. 2023

Sci Rep

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“…Increasing evidence supported by single-cell sequencing suggests a central role for energy metabolism [48]. A high metabolic rate is required to maintain the physiological functions of PTCs.…”

Section: Early Response To Injury In Proximal Tubule Cellsmentioning

confidence: 99%

“…The Ca 2þ -dependent mitochondria stress response activates a complex signalling response to the nucleus, including the activation of NFkB [51]. In parallel, a HIF1A-driven metabolic adaptation likely maintains cell viability and -in analogy with studies in cancer -contributes to major cell state changes and cell proliferation [48]. Importantly, different types of acute and chronic kidney injury elicit distinct metabolic alterations and can interfere with the mito-nuclear communication regulating fundamental cellular processes in homeostasis and in stress conditions [51,52].…”

Section: Early Response To Injury In Proximal Tubule Cellsmentioning

confidence: 99%

“…Several groups identified and characterized altered PTC states, which were not present in the kidney of normal young mice but persisted in the late states after AKI after normalization of kidney function and in experimental models of chronic kidney disease [28, PTCs represent the common final step of a failedrepair process independently of the initial type of injury and that different biological processes might contribute to the establishment of this likely irreversible cell state [28,45]. Results obtained in distinct experimental and clinical conditions suggest again a pivotal role for mitochondrial function and fatty acid metabolism along the transition from early injury to failed repair: a delicate balance in the accumulation of lipid droplets in damaged tubule cells might promote tubule repair or conversely contribute to a vicious circle of lipotoxicity [28,48,59]. The proinflammatory and profibrotic features of failed-repair PTCs are in good agreement with the senescence-associated secretory phenotype (SASP) reported in aged and injured nonkidney tissues [38].…”

Section: Altered Proximal Tubule Cells In Failed Tubule Repairmentioning

confidence: 99%

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Proximal tubule responses to injury: interrogation by single-cell transcriptomics

Cippà

McMahon

2023

Current Opinion in Nephrology &Amp; Hypertension

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Purpose of reviewAcute kidney injury (AKI) occurs in approximately 10--15% of patients admitted to hospital and is associated with adverse clinical outcomes. Despite recent advances, management of patients with AKI is still mainly supportive, including the avoidance of nephrotoxins, volume and haemodynamic management and renal replacement therapy. A better understanding of the renal response to injury is the prerequisite to overcome current limitations in AKI diagnostics and therapy. Recent findingsSingle-cell technologies provided new opportunities to study the complexity of the kidney and have been instrumental for rapid advancements in the understanding of the cellular and molecular mechanisms of AKI.

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“…To produce the adenosine triphosphate (ATP) required for active transporters, PTECs use 10% of the total oxygen consumption of the body [17]. Thus, the PT is rich in mitochondria and relies heavily on fatty acid β-oxidation (FAO) as fuel for energy [18]. The high energy dependence of PTECs renders them vulnerable to oxidative and metabolic stress, which disrupt mitochondrial function in premature renal aging [19].…”

Section: Introductionmentioning

confidence: 99%

NAD+ Metabolism and Interventions in Premature Renal Aging and Chronic Kidney Disease

Chanvillard

Tammaro

Sorrentino

2022

Cells

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Premature aging causes morphological and functional changes in the kidney, leading to chronic kidney disease (CKD). CKD is a global public health issue with far-reaching consequences, including cardio-vascular complications, increased frailty, shortened lifespan and a heightened risk of kidney failure. Dialysis or transplantation are lifesaving therapies, but they can also be debilitating. Currently, no cure is available for CKD, despite ongoing efforts to identify clinical biomarkers of premature renal aging and molecular pathways of disease progression. Kidney proximal tubular epithelial cells (PTECs) have high energy demand, and disruption of their energy homeostasis has been linked to the progression of kidney disease. Consequently, metabolic reprogramming of PTECs is gaining interest as a therapeutic tool. Preclinical and clinical evidence is emerging that NAD+ homeostasis, crucial for PTECs’ oxidative metabolism, is impaired in CKD, and administration of dietary NAD+ precursors could have a prophylactic role against age-related kidney disease. This review describes the biology of NAD+ in the kidney, including its precursors and cellular roles, and discusses the importance of NAD+ homeostasis for renal health. Furthermore, we provide a comprehensive summary of preclinical and clinical studies aimed at increasing NAD+ levels in premature renal aging and CKD.

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Immunometabolic rewiring of tubular epithelial cells in kidney disease

Cited by 46 publications

References 166 publications

Metabolomic profiling in kidney cells treated with a sodium glucose-cotransporter 2 inhibitor

Metabolomic profiling in kidney cells treated with a sodium glucose-cotransporter 2 inhibitor

Proximal tubule responses to injury: interrogation by single-cell transcriptomics

NAD+ Metabolism and Interventions in Premature Renal Aging and Chronic Kidney Disease

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