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Abstract: FR-OR36

Single-Cell Resolution Drug Effects on RAAS Blockade in ZSF1 Rat Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic

Authors

  • Balzer, Michael S., University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Zhou, Jianfu, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Abedini, Amin, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Ma, Ziyuan, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Grundmann, Manuel, Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany
  • Pavkovic, Mira, Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany
  • Susztak, Katalin, University of Pennsylvania, Philadelphia, Pennsylvania, United States
Background

Diabetic kidney disease (DKD) is the leading cause of renal failure worldwide. Overactivation of the renin-angiotensin-aldosterone system (RAAS) is associated with detrimental outcomes in DKD patients. RAAS inhibitors such as enalapril have been used for decades as antiproteinuric, antihypertensive, and kidney protective agents. Still, the exact cell type of action and the main drivers of drug action remain elusive.

Methods

To this end, in addition to detailed biochemical, histological, and tissue proteomics analysis of the ZSF1 obese rat with or without enalapril treatment, we leveraged single-cell transcriptomics (scRNA-seq). We exploited state-of-the-art analyses of unbiased tensor decomposition, differential gene expression, pathway enrichment, cell trajectories, RNA velocity, weighted gene correlation networks, integration with CITE-seq imputed antibody-derived tags, and cell-cell communication. Results from the ZSF1 model were validated in human kidney samples and datasets.

Results

RAAS inhibition via enalapril ameliorated hypertension, proteinuria, kidney tissue levels of progression markers, and fibrosis in the ZSF1 rat model of DKD. ScRNA-seq highlighted immune cell enrichment, endothelial and tubular cell depletion. Unbiased tensor decomposition analysis showed distal nephron tubule cells were associated with treatment status. Enalapril downregulated cathepsin D (Ctsd) in diabetic distal nephron and myeloid cells. Ctsd+ injured tubule cells of the distal nephron were enriched in DKD and depleted upon enalapril treatment. Ctsd was also a marker for Trem2+ residential macrophages, which demonstrated an inflammatory phenotype and interacted strongly with distal nephron tubule cells. CTSD was particularly enriched in kidneys from DKD patients and correlated with outcome-relevant parameters such as fibrosis and glomerular filtration rate.

Conclusion

We report previously unknown injury cell states of the distal nephron, describe CTSD as an important regulator of enalapril effects, and reveal Trem2+ residential macrophages as top receivers of distal nephron cell-cell communication. Finally, we show that our findings translate to humans and demonstrate that enalapril-associated gene signatures allow stratification of human kidney samples by disease-relevant outcome measures such as kidney function and fibrosis.

Funding

  • Commercial Support – Bayer