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

To elucidate the physiologic function of renal globotriaosylceramide(Gb3/CD77), which up-to-date has been associated exclusively with Shiga toxinbinding, 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 borderand within vesicular structures in WT proximal tubulesand has now been shown to be closely associated with the receptor complex megalin/ cubilinand with albumin uptake. In two clinically relevant mouse models of acute kidney injurycaused by myoglobinas seen in rhabdomyolysisand 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, myoglobinand the aminoglycoside gentamicin.