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Kidney Week

Abstract: PO0661

Transcriptional Profiling of Renal Endothelial Compartments During Progression of Murine Diabetic Nephropathy

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Zhou, Alex Xianghua, AstraZeneca Gothenburg, Gothenburg, Sweden
  • Jeansson, Marie, Karolinska Institutet, Stockholm, Sweden
  • He, Liqun, Karolinska Institutet, Stockholm, Sweden
  • Tonelius, Pernilla, AstraZeneca Gothenburg, Gothenburg, Sweden
  • Muhl, Lars, Karolinska Institutet, Stockholm, Stockholm, Sweden
  • Uhrbom, Martin, AstraZeneca Gothenburg, Gothenburg, Sweden
  • Liu, Jianping, Karolinska Institutet, Stockholm, Stockholm, Sweden
  • Granqvist, Anna, AstraZeneca Gothenburg, Gothenburg, Sweden
  • Lerman, Lilach O., Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Betsholtz, Christer, Karolinska Institutet, Stockholm, Sweden
  • Laerkegaard Hansen, Pernille B., AstraZeneca Gothenburg, Gothenburg, Sweden

Group or Team Name

  • Early CVRM Bioscience Renal
Background

Kidney endothelial cell (EC) injury and capillary rarefaction are key pathogenic events in diabetic nephropathy (DN). The molecular mechanisms and spatial and temporal patterns of EC responses in DN remain elusive. We hypothesized that single-cell RNA sequencing (scRNASeq) would reveal transcriptional changes in specific kidney EC populations during murine DN progression.

Methods

Kidney EC (n=5,464) collected from 6-, 11-, and 20-week-old BTBR ob/ob mice and lean littermates were analyzed by scRNASeq using SmartSeq2. By a combination of established markers, immunofluorescence, and in situ hybridization, we ascribed anatomical identity to EC clusters assigned by Pagoda2, assessed their individual transcriptional changes during disease progression, and performed Ingenuity Pathway Analysis.

Results

We identified EC clusters corresponding to afferent and efferent arterioles, glomerular and peritubular capillaries (PTC), ascending and descending vasa recta, veins and lymphatics. BTBR ob/ob mice developed progressive PTC rarefaction. Analysis of differentially expressed genes (DEGs) and pathway activity allocated most DN-associated changes to PTC and glomerular EC. Intriguingly, several consistent DEGs showed differential up- and downregulation depending on cell type and disease stage (Fig. 1). E.g., whereas glomerular EC showed DN stage-dependent activation of IGF1 signaling and inflammation, IGF1 signaling and cell cycle progression were inhibited in PTC-EC.

Conclusion

Using high-resolution scRNASeq, our study provides insight into the complexity and diversity of responses in different EC compartments during progression of DN, which may help pinpoint new therapeutic targets.

Funding

  • Commercial Support