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

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

doi:10.1016/j.kint.2019.02.010

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. Epub 2019 Feb 28.

Affiliations

¹ Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany. Electronic address: [email protected].
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: [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acute Kidney Injury / chemically induced
Acute Kidney Injury / drug therapy*
Acute Kidney Injury / pathology
Albumins / metabolism*
Animals
Dioxanes / pharmacology*
Dioxanes / therapeutic use
Disease Models, Animal
Galactosyltransferases / antagonists & inhibitors*
Galactosyltransferases / genetics
Galactosyltransferases / metabolism
Gentamicins / metabolism
Gentamicins / toxicity
Humans
Intravital Microscopy
Kidney Tubules, Proximal / drug effects
Kidney Tubules, Proximal / pathology
Kidney Tubules, Proximal / ultrastructure
Low Density Lipoprotein Receptor-Related Protein-2 / metabolism
Male
Mice
Mice, Knockout
Microscopy, Electron
Microscopy, Fluorescence, Multiphoton
Microvilli / drug effects
Microvilli / metabolism
Myoglobin / metabolism
Myoglobin / toxicity
Pyrrolidines / pharmacology*
Pyrrolidines / therapeutic use
Receptors, Cell Surface / metabolism
Renal Elimination / drug effects
Renal Reabsorption / drug effects*
Trihexosylceramides / metabolism*

Substances

(2-(2',3'-dihydrobenzo(1,4)dioxin-6'-yl)-2-hydroxy-1-pyrrolidin-1-ylmethylethyl)nonanoic acid amide
Albumins
Dioxanes
Gentamicins
Low Density Lipoprotein Receptor-Related Protein-2
Lrp2 protein, mouse
Myoglobin
Pyrrolidines
Receptors, Cell Surface
Trihexosylceramides
intrinsic factor-cobalamin receptor
globotriaosylceramide
Galactosyltransferases
UDP-galactose-lactosylceramide alpha 1-4-galactosyltransferase