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Abstract: TH-PO223

Comparative Transcriptomics of Human and Mouse Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Sembach, Frederikke Emilie, Gubra ApS, Hørsholm, Denmark, Denmark
  • Østergaard, Mette Viberg, Gubra ApS, Hørsholm, Denmark, Denmark
  • Nielsen, Jens Christian, Gubra ApS, Hørsholm, Denmark, Denmark
  • Christensen-Dalsgaard, Mikkel, Gubra ApS, Hørsholm, Denmark, Denmark
  • Madsen, Martin Roenn, Gubra ApS, Hørsholm, Denmark, Denmark
  • Feldt-Rasmussen, Bo, Rigshospitalet, Kobenhavn, Denmark
  • Porrini, Esteban, Hospital Universitario de Canarias, La Laguna, Canarias, Spain
  • Hornum, Mads, Rigshospitalet, Kobenhavn, Denmark
  • Fink, Lisbeth N., Gubra ApS, Hørsholm, Denmark, Denmark
Background

Transcriptome profiling is instrumental for investigating molecular mechanisms driving disease progression in diabetic kidney disease (DKD). However, a major impediment in DKD research is the scarcity of frozen kidney tissue specimens from patients with DKD. To overcome this challenge, the present study applied RNA sequencing of formalin-fixed paraffin-embedded (FFPE) kidney samples from an ongoing study in patients with DKD. The clinical translatability of an advanced DKD mouse model was assessed by comparison to the human transcriptome profile.

Methods

RNA sequencing was performed on FFPE kidney samples from patients undergoing nephrectomy as part of the European Nephrectomy BioBank project (ENBiBa). All patients included were diagnosed with obesity and hypertension and were divided into two groups based on presence of type 2 diabetes and DKD (n = 6), while nondiabetic patients with no kidney disease were included as controls (n = 8). Also, RNA sequencing was performed on snap-frozen kidney cortex samples from a model of advanced DKD facilitated by adeno-associated virus (AAV)-mediated renin overexpression in uninephrectomized (UNx) db/db mice and healthy non-diabetic db/m controls.

Results

A total of 105 differentially expressed genes (DEGs) were identified in human DKD FFPE kidney samples, when compared to the human controls. Of these DEGs, a significant overlap of 32 genes were regulated in both human DKD and db/db UNx-ReninAAV mice, including upregulation of genes associated with extracellular matrix remodelling (COL1A1, COL1A2, MMP14, VCAM1). The tubular specific marker UMOD was downregulated in both human DKD patients and in db/db UNx-ReninAAV mice, indicating tubular injury, while solute carrier family genes (SLC5A3, SLC12A1) were only downregulated in human DKD patients.

Conclusion

Identification of regulated genes associated with DKD in this cohort of patients with obesity, diabetes and chronic kidney disease confirms the applicability of RNA sequencing of FFPE samples for analysing global gene expression changes and investigating molecular mechanisms involved in the progression of DKD. Transcriptome signatures in the db/db UNx-ReninAAV mouse indicates good clinical translatability, highlighting the use of this model in preclinical DKD research.

Funding

  • Commercial Support