Renal globotriaosylceramide facilitates tubular albumin absorption and its inhibition protects against acute kidney injury

Morace, Ivan; Pilz, Robert; Federico, Giuseppina; Jennemann, Richard; Krunic, Damir; Nordström, Viola; Gerichten, Johanna von; Marsching, Christian; Schießl, Ina Maria; Müthing, Johannes; Wunder, Christian; Johannes, Ludger; Sandhoff, Roger; Gröne, Hermann–Josef

doi:10.1016/j.kint.2019.02.010

Cited by 25 publications

(19 citation statements)

References 39 publications

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“…HK-2 and ACHN cells harbor globotriaosylceramide (Gb3Cer) [58,60,62], and the various lipoforms of Stx-binding Gb3Cer of the ACHN cell line have been recently identified [65]. Furthermore, Stx-mediated cytopathic action has also been shown for primary human renal glomerular and tubular epithelial cells [66][67][68][69][70][71][72], suggesting contribution of renal epithelial cells in Stx-mediated kidney failure as previously shown in a mouse model [73,74]. To warrant functionally intact primary cells and to avoid spontaneous decay of their differential phenotype, it is mandatory to restrict the total number of cell passages (commonly ≤ 8 passages).…”

Section: Introductionmentioning

confidence: 69%

Shiga Toxin (Stx)-Binding Glycosphingolipids of Primary Human Renal Cortical Epithelial Cells (pHRCEpiCs) and Stx-Mediated Cytotoxicity

Detzner

Krojnewski

Pohlentz

et al. 2021

Toxins

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Human kidney epithelial cells are supposed to be directly involved in the pathogenesis of the hemolytic–uremic syndrome (HUS) caused by Shiga toxin (Stx)-producing enterohemorrhagic Escherichia coli (EHEC). The characterization of the major and minor Stx-binding glycosphingolipids, (GSLs) globotriaosylceramide (Gb3Cer) and globotetraosylceramide (Gb4Cer), respectively, of primary human renal cortical epithelial cells (pHRCEpiCs) revealed GSLs with Cer (d18:1, C16:0), Cer (d18:1, C22:0), and Cer (d18:1, C24:1/C24:0) as the dominant lipoforms. Using detergent-resistant membranes (DRMs) and non-DRMs, Gb3Cer and Gb4Cer prevailed in the DRM fractions, suggesting their association with microdomains in the liquid-ordered membrane phase. A preference of Gb3Cer and Gb4Cer endowed with C24:0 fatty acid accompanied by minor monounsaturated C24:1-harboring counterparts was observed in DRMs, whereas the C24:1 fatty acid increased in relation to the saturated equivalents in non-DRMs. A shift of the dominant phospholipid phosphatidylcholine with saturated fatty acids in the DRM to unsaturated species in the non-DRM fractions correlated with the GSL distribution. Cytotoxicity assays gave a moderate susceptibility of pHRCEpiCs to the Stx1a and Stx2a subtypes when compared to highly sensitive Vero-B4 cells. The results indicate that presence of Stx-binding GSLs per se and preferred occurrence in microdomains do not necessarily lead to a high cellular susceptibility towards Stx.

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Section: Introductionmentioning

confidence: 69%

Shiga Toxin (Stx)-Binding Glycosphingolipids of Primary Human Renal Cortical Epithelial Cells (pHRCEpiCs) and Stx-Mediated Cytotoxicity

Detzner

Krojnewski

Pohlentz

et al. 2021

Toxins

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“…Kidneys are particularly rich in the GSL Gb3, but its physiological function remains ill-defined. A recent study has suggested that Gb3 in the BBM of the renal proximal tubule facilitates the absorption of albumin and pharmacological inhibition of GlcCer-derived GSL synthesis, including Gb3, protects against acute kidney injury [118].…”

Section: Sphingolipids In Microvillar Protein Sorting and Targeting (mentioning

confidence: 99%

Sphingolipids controlling ciliary and microvillar function

2020

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Cilia and microvilli are membrane protrusions that extend from the surface of many different mammalian cell types. Motile cilia or flagella are only found on specialized cells, where they control cell movement or the generation of fluid flow, whereas immotile primary cilia protrude from the surface of almost every mammalian cell to detect and transduce extracellular signals. Despite these differences, all cilia consist of a microtubule core called the axoneme. Microvilli instead contain bundled linear actin filaments and are mainly localized on epithelial cells, where they modulate the absorption of nutrients. Cilia and microvilli constitute subcellular compartments with distinctive lipid and protein repertoires and specialized functions. Here, we summarize the role of sphingolipids in defining the identity and controlling the function of cilia and microvilli in mammalian cells.

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“…It may be found in endothelial cells, hematopoietic cells, pancreas, heart, liver, kidney and the CNS [ 8 ]. Although the Gb3 biological function has not been entirely elucidated yet, recent evidence suggests that it plays an essential role in protein reabsorption by renal proximal tubules [ 41 ]. Furthermore, Gb3 is the Pk antigen from the human P blood group system [ 42 , 43 ] and the CD77 antigen associated to Burkitt’s lymphoma [ 44 ]; it is also present in activated B-cells which undergo apoptosis after not being selected for plasma ce11 differentiation in germinal centers of lymphoid tissue [ 45 ].…”

Section: Stx Mechanism Of Actionmentioning

confidence: 99%

Therapeutic Strategies to Protect the Central Nervous System against Shiga Toxin from Enterohemorrhagic Escherichia coli

Goldstein

Nuñez-Goluboay

Pinto

2020

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: Infection with Shiga toxin-producing Escherichia coli (STEC) may cause hemorrhagic colitis, hemolytic uremic syndrome (HUS) and encephalopathy. The mortality rate derived from HUS adds up to 5% of the cases, and up to 40% when the central nervous system (CNS) is involved. In addition to the well-known deleterious effect of Stx, the gram-negative STEC releases lipopolysaccharides (LPS) and may induce a variety of inflammatory responses when released in the gut. Common clinical signs of severe CNS injury include sensorimotor, cognitive, emotional and/or autonomic alterations. In the last few years, a number of drugs have been experimentally employed to establish the pathogenesis of, prevent or treat CNS injury by STEC. The strategies in these approaches focus on: 1) inhibition of Stx production and release by STEC, 2) inhibition of Stx bloodstream transport , 3) inhibition of Stx entry into the CNS parenchyma , 4) blockade of deleterious Stx action in neural cells, and 5) inhibition of immune system activation and CNS inflammation. Fast diagnosis of STEC infection as well as the establishment of early CNS biomarkers of damage may be determinants of adequate neuropharmacological treatment in time.

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Renal globotriaosylceramide facilitates tubular albumin absorption and its inhibition protects against acute kidney injury

Cited by 25 publications

References 39 publications

Shiga Toxin (Stx)-Binding Glycosphingolipids of Primary Human Renal Cortical Epithelial Cells (pHRCEpiCs) and Stx-Mediated Cytotoxicity

Shiga Toxin (Stx)-Binding Glycosphingolipids of Primary Human Renal Cortical Epithelial Cells (pHRCEpiCs) and Stx-Mediated Cytotoxicity

Sphingolipids controlling ciliary and microvillar function

Therapeutic Strategies to Protect the Central Nervous System against Shiga Toxin from Enterohemorrhagic Escherichia coli

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