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Abstract: FR-OR13

Multi-Omics Identifies CERS6 and C16:0 Ceramide in Podocytes as Novel Therapeutic Targets for Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Zhang, Guanshi, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
  • Velickovic, Dusan, Pacific Northwest National Laboratory, Richland, Washington, United States
  • Pamreddy, Annapurna, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
  • Nair, Viji, University of Michigan, Ann Arbor, Michigan, United States
  • Lake, Blue, University of California San Diego, La Jolla, California, United States
  • Venkatachalam, Manjeri A., The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
  • Kretzler, Matthias, University of Michigan, Ann Arbor, Michigan, United States
  • Anderton, Christopher R., The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
  • Alexandrov, Theodore, University of California San Diego, La Jolla, California, United States
  • Sharma, Kumar, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States

Group or Team Name

  • for the KPMP Consortium
Background

Dysregulated renal ceramide (Cer)/sphingomyelin (SM) metabolism has been reported in human and animal models of diabetic kidney disease (DKD). However, there have been limited investigations in understanding the roles of Cer/SM in the pathogenesis of podocyte dysfunction. To understand the role of sphingolipid metabolism in normal and diabetic kidneys, we integrated matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) data to single nucleus Droplet-based sequencing (snDrop-Seq) and single-cell RNA sequencing (scRNA-Seq) data for a network analysis of a tabulated list of 48 Cer/SM metabolism-related gene/enzymes.

Methods

Two MALDI-MSI platforms (QE-HFX and FTICR) were employed to characterize the lipid profile in normal human kidney tissues (n = 6; U. Michigan) in situ (spatial resolution: 20-30 μm). Same tissues were also processed by snDrop-Seq analysis for multi-omics data integration. To compare kidney scRNA-Seq profiles between DKD patients and healthy controls, patient kidney biopsies (n = 44) from an early DKD cohort were collected and 18 living donor (LD) biopsies were used as reference healthy tissues.

Results

Among 30 different cell types identified by snDrop-seq, we found that CERS6 was specifically expressed in podocytes of the normal human kidney. Fluorescence microscopy analysis showed that CERS6 protein is co-localized with synaptopodin (a podocyte marker). In addition, MALDI-MSI data showed that the downstream C16:0 ceramide of CERS6 was specifically enriched in podocytes of normal human kidney biopsy tissues. scRNA-seq data of kidney biopsy tissues from LD controls and DKD patients showed that CERS6 gene was exclusively enriched in podocytes of normal human kidney biopsies (LD), while no CERS6 expression was detected in DKD biopsies, suggesting the potential role of CERS6 in regulating kidney functions.

Conclusion

This highlights the value of kidney atlas for healthy and diseased kidneys on the single cell levels of genes and metabolites in the kidney precision medicine. Multi-omics techniques could help identify novel therapeutic targets for different types of kidney diseases.

Funding

  • NIDDK Support