Albumin-associated free fatty acids induce macropinocytosis in podocytes

Chung, Jun-Jae; Huber, Tobias B.; Gödel, Markus; Jarad, George; Hartleben, Björn; Kwoh, Christopher; Keil, Alexander; Karpitskiy, Aleksey; Jiancheng, Hu; Huh, Christine J.; Cella, Marina; Gross, Richard W.; Miner, Jeffrey H.; Shaw, Andréy S.

doi:10.1172/jci79641

Cited by 74 publications

(76 citation statements)

References 59 publications

(73 reference statements)

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“…GPCR signalling leads to the triggering of the Gβ/Gγ subunits and their dissociation, which in turn activate the RHO GTPases RAC1 and CDC42, leading to disruption of the actin cytoskeleton and dramatic changes in podocyte morphology. Furthermore, compared to mice fed control chow, those fed a high-fat diet develop elevated levels of free fatty acids and an increased susceptibility to adriamycin-induced proteinuria, which underscores the effect of free fatty acids on podocyte function 99,100 . In addition, exposure of podocytes to albumin and its associated factors, such as fatty acids, has been shown to induce cell death, disruption of the cytoskeleton and injurious molecular responses, such as increased production of cyclooxygenase 2 (COX2) and several cytokines 101 .…”

Section: Dyslipidaemia In Nephrotic Syndromementioning

confidence: 96%

“…Several different free fatty acids bound to albumin have been shown to increase podocyte injury, by stimulating enhanced macropinocytosis by podocytes via lipid-binding G-protein-coupled receptors (GPCRs) 99,100 . GPCR signalling leads to the triggering of the Gβ/Gγ subunits and their dissociation, which in turn activate the RHO GTPases RAC1 and CDC42, leading to disruption of the actin cytoskeleton and dramatic changes in podocyte morphology.…”

Section: Dyslipidaemia In Nephrotic Syndromementioning

confidence: 99%

“…The mechanism by which lipid apheresis leads to remission remains unclear, but possible explanations include direct effects associated with improved dyslipidaemia, the removal of pathogenic vascular permeability factors and/or enhancement of the response to immunosuppressants 62 . One potential but unexplored hypothesis is that lipid apheresis, by lowering the level of free fatty acids, could reduce or prevent podocyte damage and reduce proteinuria 99 .…”

Section: Treatment Of Dyslipidaemiamentioning

confidence: 99%

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Dyslipidaemia in nephrotic syndrome: mechanisms and treatment

et al. 2017

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Nephrotic syndrome is a highly prevalent disease that is associated with high morbidity despite notable advances in its treatment. Many of the complications of nephrotic syndrome, including the increased risk of atherosclerosis and thromboembolism, can be linked to dysregulated lipid metabolism and dyslipidaemia. These abnormalities include elevated plasma levels of cholesterol, triglycerides and the apolipoprotein B containing lipoproteins VLDL and IDL; decreased lipoprotein lipase activity in the endothelium, muscle and adipose tissues; decreased hepatic lipase activity; and increased levels of the enzyme PCSK9. In addition, there is an increase in the plasma levels of immature HDL particles and reduced cholesterol efflux. Studies from the past few years have markedly improved our understanding of the molecular pathogenesis of nephrotic syndrome associated dyslipidaemia, and also heightened our awareness of the associated exacerbated risks of cardiovascular complications, progressive kidney disease and thromboembolism. Despite the absence of clear guidelines regarding treatment, various strategies are being increasingly utilized, including statins, bile acid sequestrants, fibrates, nicotinic acid and ezetimibe, as well as lipid apheresis, which seem to also induce partial or complete clinical remission of nephrotic syndrome in a substantial percentage of patients. Future potential treatments will likely also include inhibition of PCSK9 using recently developed anti PCSK9 monoclonal antibodies and small inhibitory RNAs, as well as targeting newly identified molecular regulators of lipid metabolism that are dysregulated in nephrotic syndrome.

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Section: Dyslipidaemia In Nephrotic Syndromementioning

confidence: 96%

Section: Dyslipidaemia In Nephrotic Syndromementioning

confidence: 99%

Section: Treatment Of Dyslipidaemiamentioning

confidence: 99%

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Dyslipidaemia in nephrotic syndrome: mechanisms and treatment

et al. 2017

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“…Furthermore, in adriamycin‐treated mice, albumin endocytosis and albuminuria were increased in animals fed a high fat diet (which increased plasma free fatty acids) compared with mice receiving a standard chow (Chung et al . ).…”

Section: Endocytosis Of Plasma Proteins By Podocytesmentioning

confidence: 97%

“…Recent data obtained in vivo suggest that free fatty acids associated with albumin facilitate the fluid phase uptake of albumin by podocytes (Chung et al 2015). Furthermore, this macropinocytosis involved the binding of free fatty acids to corresponding receptors, such as FFAR1, FFAR2 and FFAR3.…”

Section: Endocytosis Of Plasma Proteins By Podocytesmentioning

confidence: 97%

Novel routes of albumin passage across the glomerular filtration barrier

Castrop

Schießl

2016

Acta Physiologica

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Albuminuria is a hallmark of kidney diseases of various aetiologies and an unambiguous symptom of the compromised integrity of the glomerular filtration barrier. Furthermore, there is increasing evidence that albuminuria per se aggravates the development and progression of chronic kidney disease. This review covers new aspects of the movement of large plasma proteins across the glomerular filtration barrier in health and disease. Specifically, this review focuses on the role of endocytosis and transcytosis of albumin by podocytes, which constitutes a new pathway of plasma proteins across the filtration barrier. Thus, we summarize what is known about the mechanisms of albumin endocytosis by podocytes and address the fate of the endocytosed albumin, which is directed to lysosomal degradation or transcellular movement with subsequent vesicular release into the urinary space. We also address the functional consequences of overt albumin endocytosis by podocytes, such as the formation of pro-inflammatory cytokines, which might eventually result in a deterioration of podocyte function. Finally, we consider the diagnostic potential of podocyte-derived albumin-containing vesicles in the urine as an early marker of a compromised glomerular barrier function. In terms of new technical approaches, the review covers how our knowledge of the movement of albumin across the glomerular filtration barrier has expanded by the use of new intravital imaging techniques.

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Attacking the supply wagons to starve cancer cells to death

et al. 2016

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The constitutive anabolism of cancer cells supports proliferation but also addicts tumor cells to a steady influx of exogenous nutrients. Limiting access to metabolic substrates could be an effective and selective means to block cancer growth. In this review, we define the pathways by which cancer cells acquire the raw materials for anabolism, highlight the actionable proteins in each pathway, and discuss the status of therapeutic interventions that disrupt nutrient acquisition. Critical open questions to be answered before apical metabolic inhibitors can be successfully and safely deployed in the clinic are also outlined. In summary, recent studies provide strong support that substrate limitation is a powerful therapeutic strategy to effectively, and safely, starve cancer cells to death.

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Albumin-associated free fatty acids induce macropinocytosis in podocytes

Cited by 74 publications

References 59 publications

Dyslipidaemia in nephrotic syndrome: mechanisms and treatment

Dyslipidaemia in nephrotic syndrome: mechanisms and treatment

Novel routes of albumin passage across the glomerular filtration barrier

Attacking the supply wagons to starve cancer cells to death

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