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.糖尿病肾病（Diabetic Kidney Disease，DKD）是全球范围内引发肾衰竭的首要病因。肾素-血管紧张素-醛固酮系统（Renin Angiotensin-Aldosterone System，RAAS）的过度激活与DKD患者的不良预后密切相关。以依那普利为代表的RAAS抑制剂已被应用数十年，用作抗蛋白尿、降血压及肾脏保护药物。然而，该药物的确切作用细胞类型及核心作用机制仍不明晰。本研究借助最先进的单细胞转录组学技术，以ZSF1肥胖大鼠为模型，旨在阐明依那普利发挥药效的潜在靶细胞与核心调控分子。本研究首次揭示了远端肾小管此前未被报道的损伤细胞状态，明确组织蛋白酶D（Cathepsin D，Ctsd）是依那普利药效的重要调控因子，并证实Trem2阳性常驻巨噬细胞是远端肾小管细胞间通讯的主要接收者。最后，本研究证明上述发现可转化至人类研究，并表明依那普利相关基因特征可依据肾功能、纤维化等与疾病相关的预后指标，对人类肾脏样本进行分层分型。