2. Academic Validation
  3. Renal globotriaosylceramide facilitates tubular albumin absorption and its inhibition protects against acute kidney injury

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

  • Kidney Int. 2019 Aug;96(2):327-341. doi: 10.1016/j.kint.2019.02.010.
Ivan Morace 1,  Robert Pilz 2,  Giuseppina Federico 3,  Richard Jennemann 3,  Damir Krunic 4,  Viola Nordström 3,  Johanna von Gerichten 2,  Christian Marsching 2,  Ina Maria Schießl 5,  Johannes Müthing 6,  Christian Wunder 7,  Ludger Johannes 7,  Roger Sandhoff 2,  Hermann-Josef Gröne 8
Affiliations

Affiliations

  • 1 Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany. Electronic address: imorace.jr@gmail.com.
  • 2 Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany; Lipid Pathobiochemistry Group, German Cancer Research Center, Heidelberg, Germany.
  • 3 Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.
  • 4 Light Microscopy Facility, German Cancer Research Center, Heidelberg, Germany.
  • 5 Institute of Physiology, University of Regensburg, Regensburg, Germany.
  • 6 Institute for Hygiene, University of Münster, Münster, Germany.
  • 7 Institut Curie, PSL Research University, Chemical Biology of Membranes and Therapeutic Delivery Unit, CNRS UMR3666, INSERM U1143, Paris, France.
  • 8 Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany; Institute of Pharmacology, University of Marburg, Marburg, Germany. Electronic address: hgroene@mailbox.org.
PMID: 31101366 DOI: 10.1016/j.kint.2019.02.010
Abstract

To elucidate the physiologic function of renal globotriaosylceramide (Gb3/CD77), which up-to-date has been associated exclusively with Shiga toxin binding, we have analyzed renal function in Gb3-deficient mice. Gb3 synthase KO (Gb3S-/-) mice displayed an increased renal albumin and low molecular weight protein excretion compared to WT. Gb3 localized at the brush border and within vesicular structures in WT proximal tubules and has now been shown to be closely associated with the receptor complex megalin/cubilin and with albumin uptake. In two clinically relevant mouse models of acute kidney injury caused by myoglobin as seen in rhabdomyolysis and the Aminoglycoside gentamicin, Gb3S-/- mice showed a preserved renal function and morphology, compared to WT. Pharmacologic inhibition of glucosylceramide-based glycosphingolipids, including Gb3, in WT mice corroborated the results of genetically Gb3-deficient mice. In conclusion, our data significantly advance the current knowledge on the physiologic and pathophysiologic role of Gb3 in proximal tubules, showing an involvement in the reabsorption of filtered albumin, myoglobin and the Aminoglycoside gentamicin.

Keywords

acute kidney injury; endocytosis; gentamicin; globotriaosylceramide; rhabdomyolysis.

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