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

Key Points Cathepsin D regulated enalapril effects in distal nephron injury states of diabetic kidney disease. Enalapril reduced proinflammatory triggering receptor expressed on myeloid cells 2+ macrophages interacting with distal nephron cells. Enalapril-associated gene signatures stratified human kidneys by fibrosis and function outcomes. Background Diabetic kidney disease is the leading cause of kidney failure worldwide. Renin-angiotensin-aldosterone system 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 Zucker spontaneously hypertensive fatty 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, a tissue renin-angiotensin-aldosterone system effector, as an important regulator of enalapril effects and revealed triggering receptor expressed on myeloid cells 2+ 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 cathepsin D as an important regulator of enalapril effects, involving cross-talk between the distal nephron and triggering receptor expressed on myeloid cells 2+ residential macrophages. We also demonstrated that enalapril-associated gene signatures allow stratification of human kidney samples by disease-relevant outcome measures.