Sugar or Fat? Renal Tubular Metabolism Reviewed in Health and Disease

Gewin, Leslie

doi:10.3390/nu13051580

Cited by 69 publications

(64 citation statements)

References 96 publications

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“…A decreased TCA-cycle flux might also explain accumulating citrate levels. The decrease in acyl-carnitines further supports this hypothesis, since fatty acid oxidation is a predominant energy source in tubule cells [ 27 ]. An elevated usage of glucose also fits with the accumulation of sorbitol in tubule cells [ 25 ].…”

Section: Resultsmentioning

confidence: 64%

Metabolic and Lipidomic Assessment of Kidney Cells Exposed to Nephrotoxic Vancomycin Dosages

Lagies

Pichler

Vladimirov

et al. 2021

IJMS

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Vancomycin is a glycopeptide antibiotic used against multi-drug resistant gram-positive bacteria such as Staphylococcus aureus (MRSA). Although invaluable against resistant bacteria, vancomycin harbors adverse drug reactions including cytopenia, ototoxicity, as well as nephrotoxicity. Since nephrotoxicity is a rarely occurring side effect, its mechanism is incompletely understood. Only recently, the actual clinically relevant concentration the in kidneys of patients receiving vancomycin was investigated and were found to exceed plasma concentrations by far. We applied these clinically relevant vancomycin concentrations to murine and canine renal epithelial cell lines and assessed metabolic and lipidomic alterations by untargeted and targeted gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry analyses. Despite marked differences in the lipidome, both cell lines increased anabolic glucose reactions, resulting in higher sorbitol and lactate levels. To the best of our knowledge, this is the first endometabolic profiling of kidney cells exposed to clinically relevant vancomycin concentrations. The presented study will provide a valuable dataset to nephrotoxicity researchers and might add to unveiling the nephrotoxic mechanism of vancomycin.

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Section: Resultsmentioning

confidence: 64%

Metabolic and Lipidomic Assessment of Kidney Cells Exposed to Nephrotoxic Vancomycin Dosages

Lagies

Pichler

Vladimirov

et al. 2021

IJMS

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“…In addition, the HK-2 cells that were used in our present work were considered more likely to be epithelial cells than the native proximal tubule cells, which was demonstrated by researchers using RNA-sequencing and proteomics. Since it is known that the native proximal tubule cells use fatty acids, but not glucose, as the energy source [ 54 ], it is necessary to elucidate the distinctive characteristics in the different kinds of renal cells in detail within subsequent works. In the future, this strategy will hopefully be applied to in vivo studies related to CKD (either animal models or clinical patients), as well as other metabolic diseases that are involved in oxidative stress and lipid dysregulation.…”

Section: Resultsmentioning

confidence: 99%

“…energy source [54], it is necessary to elucidate the distinctive characteristics in the different kinds of renal cells in detail within subsequent works. In the future, this strategy will hopefully be applied to in vivo studies related to CKD (either animal models or clinical patients), as well as other metabolic diseases that are involved in oxidative stress and lipid dysregulation.…”

Section: Lipid Hydroperoxidation Caused By Oxidized Lipoprotein Treat...mentioning

confidence: 99%

Oxidative Stress and Lipid Dysregulation in Lipid Droplets: A Connection to Chronic Kidney Disease Revealed in Human Kidney Cells

et al. 2022

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Chronic kidney disease (CKD), which is defined as a condition causing the gradual loss of kidney function, shows renal lipid droplet (LD) accumulation that is associated with oxidative damage. There is a possibility that an LD abnormality in quality plays a role in CKD development. This study aimed to explore the chemical composition of LDs that are induced in human kidney cells during exposure to free fatty acids as an LD source and oxidized lipoproteins as oxidative stress. The LDs were aspirated directly from cells using nanotips, followed by in-tip microextraction, and the LD lipidomic profiling was conducted using nanoelectrospray mass spectrometry. As a result, the free fatty acids increased the LD lipid content and, at the same time, changed their composition significantly. The oxidized lipoproteins caused distorted proportions of intact lipids, such as triacylglycerols (TG), phosphatidylcholines (PC), phosphatidylethanolamines (PE), and cholesteryl esters (CE). Notably, the oxidized lipids, including the hydroperoxides of TG, PC, and PE, exhibited significant elevations in dose-dependent manners. Furthermore, the dysregulation of intact lipids was paralleled with the accumulation of lipid hydroperoxides. The present study has revealed that the oxidation of lipids and the dysregulation of the lipid metabolism coexisted in LDs in the kidney cells, which has provided a potential new target for diagnosis and new insights into CKD.

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“…Although fatty acid oxidation (FAO) is considered the main energyproducing mechanism in proximal tubules 104 , mitochondrial glucose and glutamine utilization are also crucial for the kidney cell homeostasis [105][106][107] . In DKD, defective renal FAO is accompanied by increased glycolysis and altered glutamine metabolism [108][109][110] . A higher influx of glucose to kidney cells may compromise the balance between the mitochondrial and glycolytic fates of glucose, resulting in enhanced lactate secretion.…”

Section: Discussionmentioning

confidence: 99%

Cell Sex and Sex Hormones Modulate Kidney Glucose and Glutamine Metabolism in Health and Diabetes

Clotet-Freixas

Zaslaver

Pastrello

et al. 2021

Preprint

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Male sex is a risk factor for progression of diabetic kidney disease, but the reasons for this predilection are unclear. Here, we demonstrate that cell sex and sex hormones alter the metabolic phenotype of human proximal tubular epithelial cells (PTECs). Male PTECs displayed increased glycolysis, mitochondrial respiration, oxidative stress, apoptosis, and high glucose-induced injury, compared to female PTECs. This phenotype was enhanced by dihydrotestosterone (DHT) and linked to increased mitochondrial utilization of glucose and glutamine. Studies in vivo pointed towards increased glutamine anaplerosis in diabetic male kidneys. Male sex was linked to increased levels of glutamate, TCA cycle, and glutathione cycle metabolites, in PTECs and in the blood metabolome of healthy youth and youth with type 2 diabetes. Conversely, female PTECs displayed increased levels of pyruvate, glutamyl-cysteine, cysteinylglycine, and a higher GSH/GSSG ratio than male PTECs, indicative of enhanced redox homeostasis. Finally, we identified transcriptional mechanisms that control kidney metabolism in a sex-specific fashion. While X-linked demethylase KDM6A facilitated metabolic homeostasis in female PTECs, transcription factor HNF4A mediated the deleterious effects of DHT in male PTECs. This work uncovers the role of sex in glucose/glutamine metabolism, that may explain the roots of sex dimorphism in the healthy and diabetic kidney.

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Sugar or Fat? Renal Tubular Metabolism Reviewed in Health and Disease

Cited by 69 publications

References 96 publications

Metabolic and Lipidomic Assessment of Kidney Cells Exposed to Nephrotoxic Vancomycin Dosages

Metabolic and Lipidomic Assessment of Kidney Cells Exposed to Nephrotoxic Vancomycin Dosages

Oxidative Stress and Lipid Dysregulation in Lipid Droplets: A Connection to Chronic Kidney Disease Revealed in Human Kidney Cells

Cell Sex and Sex Hormones Modulate Kidney Glucose and Glutamine Metabolism in Health and Diabetes

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