Kidney Week

Abstract: FR-PO296

Single-Nucleus RNA Sequencing Reveals Sex-Specific Renoprotective Mechanisms in Diabetic Kidney Disease

Session Information

• Diabetic Kidney Disease: Basic - 1
  October 25, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 701 Diabetic Kidney Disease: Basic

Authors

• Liu, Shuya, III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Shuya Liu, PhD

• Zhang, Tianran, III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Tianran Zhang

• Lu, Shun, III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Shun Lu, PhD

• Strauch, Martin, Institute of Pathology, RWTH Aachen University Clinic, Aachen, Germany

Martin Strauch, PhD

• Goedertier, Michaël, Institute for Computational Genomics, RWTH Aachen University Clinic, Aachen, Germany

Michaël Goedertier, MSc

• Costa, Ivan, Institute for Computational Genomics, RWTH Aachen University Clinic, Aachen, Germany

Ivan Costa

• Boor, Peter, Institute of Pathology, RWTH Aachen University Clinic, Aachen, Germany

Peter Boor, MD, PhD

• Bonn, Stefan, Institute of Medical Systems Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Stefan Bonn, PhD

• Huber, Tobias B., III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Tobias B. Huber, MD, FASN

Background

Diabetic kidney disease (DKD) is a major complication of diabetes and the leading cause of end-stage renal disease worldwide. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) and angiotensin receptor blockers (ARB) have shown promise in preventing DKD progression, but their molecular mechanisms remain to be elucidated.

Methods

We treated DKD mice (BTBR ob/ob) with SGLT2i, ARB or their combination for 12 weeks. Healthy BTBR wild-type and vehicle-treated BTBR ob/ob mice served as controls. Notably, only female DKD mice showed significantly reduced albuminuria across all treatments. To explore the mechanisms, single-nucleus RNA sequencing (snRNA-seq) was performed on kidneys from female mice in each group (n=2/group).

Results

A total of 98,684 single nuclei were identified, which were characterized into 22 clusters and classified into 12 meta-cell types. Differential gene expression analysis was performed to define treatment responsive and non-responsive genes in each meta-cell type. Proximal tubule epithelial cells showed the most significant treatment response, whereas glomerular cell types showed limited responses. CellChat was used to identify renoprotective intercellular communication networks. Pattern recognition showed that proximal tubule epithelial and glomerular cells emerged as key signaling sources, suggesting their crucial role. The limited glomerular response suggests that current therapies may not fully address the disease in these cells. To identify potential therapeutic targets, Drug2Cell was used to predict glomerular cell-specific drug targets for each treatment, highlighting critical signaling pathways and offering insights for future drug development.

Conclusion

This study presents a comprehensive snRNA-seq analysis of female DKD mice treated with SGLT2i and ARB, revealing differential treatment responses by cell type. Intercellular communication networks highlight the importance of glomerular targeting and the discovery of novel drug targets for improved glomerular protection. Future work will integrate the framework for large-scale histomorphometry (FLASH) to correlate morphological lesions with the snRNA-seq data, aiming to provide a more comprehensive picture of DKD treatment at both transcriptomic and morphological levels.

Funding

• Government Support – Non-U.S.