Abstract: SA-PO0260
Gb3S Deficiency Protects Against Diabetic Kidney Disease and Cisplatin-Induced AKI
Session Information
- AKI: Mechanisms - Cell Signaling
October 24, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Ramakrishnan, Suresh K, UniversitatsKlinikum Heidelberg, Heidelberg, Germany
- Naik, Shruti, UniversitatsKlinikum Heidelberg, Heidelberg, Germany
- Dibra, Indira, UniversitatsKlinikum Heidelberg, Heidelberg, Germany
- Loza Valdes, Angel, UniversitatsKlinikum Heidelberg, Heidelberg, Germany
- Rickert-Zacharias, Verena, UniversitatsKlinikum Heidelberg, Heidelberg, Germany
- Sandhoff, Roger, Deutsches Krebsforschungszentrum, Heidelberg, BW, Germany
- Groene, Hermann-Josef, Deutsches Krebsforschungszentrum, Heidelberg, BW, Germany
- Susztak, Katalin, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Simons, Matias, UniversitatsKlinikum Heidelberg, Heidelberg, Germany
Background
Globotriaosylceramide (Gb3) is a glycosphingolipid formed by the addition of a galactose molecule to lactosylceramide by Gb3 synthase (Gb3S), which is encoded by the A4GALT gene. Genome-wide association studies (GWAS) identified a human single nucleotide polymorphism (SNP), rs5751348, whose C allele is associated with increased tubular A4GALT expression and higher estimated glomerular filtration rates (eGFR). The C allele is also associated with higher blood glucose levels, as measured by glycated hemoglobin (HbA1c). We therefore aimed at validating the A4GALT gene variant effects in the kidney by using Gb3S KO mouse and cell culture models.
Methods
In vitro: Gb3S WT scramble, knockout (KO) and overexpression (OE) cells were generated in HK2 and hRPTEC cells and subjected to cisplatin uptake, TGFB1 treatment, transcriptomic and transepithelial electrical resistance (TEER) analyses. In vivo: Diabetes was induced in Gb3S WT and KO mice using STZ and a high-fat SFA diet. Single or repetitive cisplatin treatments were used to generate acute and chronic kidney disease, respectively. Phenotyping was performed histopathological analysis as well as blood/urinary parameters and kidney function/damage markers measurements.
Results
At baseline, Gb3S KO hRPTEC and HK2 cells took up less cisplatin and expressed more epithelial-to-mesenchymal (EMT) markers, which was augmented by TGFB1 addition. Overexpression of Gb3S in polarized flow-exposed hRPTEC cells resulted in higher TEER. KO mice exhibited more kidney fibrosis and higher blood creatinine levels in the cisplatin-induced CKD model, while, in the AKI model, KO mice showed higher GFR and significantly lower kidney damage. In the diabetes model, KO mice had lower blood HbA1c levels, less kidney damage, lower albuminuria, and glucosuria. In addition, lipid droplet content in the proximal tubules was strongly reduced compared to WT mice.
Conclusion
Our mouse and cell culture studies provide functional support for both the GFR and the HbA1c association of rs5751348. While Gb3S promotes a more robust renal epithelial phenotype that may be important for regeneration from chronic injury, its deficiency protects against cisplatin-induced AKI. Furthermore, loss of Gb3S alleviates kidney damage in DKD, potentially by more general antidiabetic effects. Thus, Gb3S depletion may be a suitable therapeutic strategy in cisplatin-mediated AKI and diabetes.