Single-cell resolution drug effects on renin-angiotensin-aldosterone blockade in ZSF1 rat diabetic kidney disease

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 are elusive. Here, we leverage state-of-the-art single-cell transcriptomics in the ZSF1 obese rat to elucidate potential target cells and driver molecules exerting enalapril drug effects. We report previously unknown injury cell states of the distal nephron, describe cathepsin D (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. Overall design: Single cells were isolated from ZSF1 rat kidneys. N=4 Lean, n=4 Obese, n=3 Obese+enalapril