Single-Cell Resolution Drug Effects of Renin-Angiotensin-Aldosterone Blockade in ZSF1 Rat Diabetic Kidney Disease

Background: Diabetic kidney disease (DKD) is the leading cause of kidney failure worldwide. Renin angiotensin-aldosterone system (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 molecular mechanism of drug action are elusive. Previous work has primarily emphasized injury patterns in the proximal nephron, leaving potential contributions of other nephron segments insufficiently characterized. Methods: Here, we leveraged state-of-the-art single-cell transcriptomics in the ZSF1 obese rat to elucidate potential target cells and driver molecules exerting enalapril drug effects. Results: We identified injured cell states of the distal nephron in the context of prolonged enalapril treatment. We showed cathepsin D (Ctsd), a tissue RAAS effector, as an important regulator of enalapril effects and revealed Trem2+ residential macrophages as top receivers of distal nephron-derived signals. Finally, we showed that enalapril-associated gene signatures allow stratification of human kidney samples by disease-relevant outcome measures such as kidney function and fibrosis. Conclusions: We reported CTSD as an important regulator of enalapril effects, involving crosstalk between the distal nephron and TREM2+ residential macrophages. We also demonstrated that enalapril-associated gene signatures allow stratification of human kidney samples by disease-relevant outcome measures.