Tubular catabolism of albumin is associated with the release of an inflammatory lipid

Kees-Folts, Deborah; Sadow, Jenny Levis; Schreiner, George F.

doi:10.1038/ki.1994.222

Cited by 134 publications

(69 citation statements)

References 29 publications

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“…Studies using these models have suggested that the proteinuria itself could induce the progressive interstitial injury, and several hypotheses have been proposed as potential mechanisms of proteinuria-induced tubulointerstitial injury. These include direct tubulotoxicity of high protein concentrations (18) or that specific proteins such as growth factors, lipoproteins (19,20), transferrin (21), or activated complement components (22, 23) may be damaging. Recent studies have emphasized the role of the MAC.…”

Section: Discussionmentioning

confidence: 99%

Complement Activation Contributes to Both Glomerular and Tubulointerstitial Damage in Adriamycin Nephropathy in Mice

Turnberg

Lewis

Moss

et al. 2006

The Journal of Immunology

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Adriamycin nephropathy is a model of focal segmental glomerulosclerosis, characterized by proteinuria and progressive glomerulosclerosis and tubulointerstitial damage. In this study, we examined the role of complement in the etiology of adriamycin nephropathy in mice. We used mice deficient in C1q, factor D, C3, and CD59, and compared them with strain-matched controls. C3 deposition occurred in the glomeruli of wild-type mice as early as 48 h following a single i.v. injection of adriamycin. C3-deficient mice developed significantly less proteinuria and less podocyte injury at day 3 postadriamycin than controls, suggesting that complement is important in mediating the early podocyte injury. At later time points, C3-deficient mice were protected from glomerulosclerosis, tubulointerstitial injury, and renal dysfunction. Factor D-deficient mice were also protected from renal disease, confirming the importance of alternative pathway activation in this model. In contrast, C1q-deficient mice developed similar disease to controls, indicating that the complement cascade was not activated via the classical pathway. CD59-deficient mice, which lack adequate control of C5b-9 formation, developed significantly worse histological and functional markers of renal disease than controls. Interestingly, although more C9 deposited in glomeruli of CD59-deficient mice than controls, in neither group was tubulointerstitial C9 staining apparent. We have demonstrated for the first time that alternative pathway activation of complement plays an important role in mediating the initial glomerular damage in this in vivo model of focal segmental glomerulosclerosis. Lack of CD59, which regulates the membrane attack complex, led to greater glomerular and tubulointerstitial injury.

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Section: Discussionmentioning

confidence: 99%

Complement Activation Contributes to Both Glomerular and Tubulointerstitial Damage in Adriamycin Nephropathy in Mice

Turnberg

Lewis

Moss

et al. 2006

The Journal of Immunology

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“…Compounds that are bound to albumin, such as free fatty acids (FFA), instead have been implicated to be causative in proinflammatory activation or injury of cultured proximal tubular cells (33). Kees-Folts et al (34), by studying the specific response of cultured tubular cells to albumin-bound molecules, found that the tubular metabolism of albumin-bound fatty acids could generate macrophage chemotactic activity, whereas delipidated albumin produced little such activity. It was suggested that fatty acids can be released during degradation of albumin, HDL, or LDL.…”

Section: Glomerular Proteinuria As Signal For Interstitial Inflammatimentioning

confidence: 99%

How Does Proteinuria Cause Progressive Renal Damage?

Abbate

Zoja

Remuzzi

2006

Journal of the American Society of Nephrology

680

533

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“…This lipid accumulation results in considerable metabolic perturbation (18). Proximal tubular segments exposed to FA-bearing albumin but not FA-free albumin elaborate a lipid chemoattractant that has a potentially key role in the induction of interstitial inflammation (19).…”

Section: Njb18@leacukmentioning

confidence: 99%

Stimulation of Proximal Tubular Cell Apoptosis by Albumin-Bound Fatty Acids Mediated by Peroxisome Proliferator Activated Receptor-γ

Arıcı¹,

Chana²,

Lewington³

et al. 2003

Journal of the American Society of Nephrology

119

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Abstract. In nephrotic syndrome, large quantities of albumin enter the kidney tubule. This albumin carries with it a heavy load of fatty acids to which the proximal tubule cells are exposed at high concentration. It is postulated that exposure to fatty acids in this way is injurious to proximal tubule cells. This study has examined the ability of fatty acids to interact with peroxisome proliferator-activated receptors (PPAR) in primary cultures of human proximal tubule cells. Luciferase reporter assays in transiently transfected human proximal tubule cells were used to show that albumin bound fatty acids and other agonists activate PPAR␥ in a dose-dependent manner. One of the consequences of this activation is apoptosis of the cells as determined by changes in cell morphology, evidence of PARP cleavage, and appearance of DNA laddering. Overexpression of PPAR␥ in these cells also results in enhanced apoptosis. Both fatty acid-induced PPAR activation and apoptosis in these cells can be blocked by PPAR response element decoy oligonucleotides. Activation of PPAR␥ by the specific agonist PGJ 2 is associated with inhibition of cell proliferation, whereas activation by albumin bound fatty acids is accompanied by increased proliferation. However, the net balance of apoptosis/proliferation favors deletion of cells. These results implicate albumin-bound fatty acids as important mediators of tubular injury in nephrosis and provide fresh impetus for pursuit of lipid-lowering strategies in proteinuric renal disease.

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Tubular catabolism of albumin is associated with the release of an inflammatory lipid

Cited by 134 publications

References 29 publications

Complement Activation Contributes to Both Glomerular and Tubulointerstitial Damage in Adriamycin Nephropathy in Mice

Complement Activation Contributes to Both Glomerular and Tubulointerstitial Damage in Adriamycin Nephropathy in Mice

How Does Proteinuria Cause Progressive Renal Damage?

Stimulation of Proximal Tubular Cell Apoptosis by Albumin-Bound Fatty Acids Mediated by Peroxisome Proliferator Activated Receptor-γ

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