Non-alcoholic fatty liver disease exacerbates the advancement of renal fibrosis by modulating renal CCR2+PIRB+ macrophages through the ANGPTL8/PIRB/ALOX5AP axis

Renal fibrosis is a key pathological feature of chronic kidney disease, and non-alcoholic fatty liver disease (NAFLD) is associated with its progression. Our previous experimental results indicate that NAFLD exacerbates UUO-induced renal fibrosis. However, the specific role and mechanisms of NAFLD in renal fibrosis remain unclear. To further investigate the underlying mechanisms, we used single-cell transcriptome sequencing to construct a single-cell atlas of the kidney. Single-cell RNA sequencing analysis and our further experimental results showed that high-fat-induced hepatocytes releasing significant levels of ANGPTL8, which activates renal CCR2+PIRB+ macrophages. These specialized macrophages promote the activation and proliferation of Th17 cells, which could further worsen renal fibrosis. The ANGPTL8/PIRB/ALOX5AP axis is thus a crucial signaling pathway between the liver and kidneys, with CCR2+PIRB+ macrophages playing a pivotal role in the progression of NAFLD-induced renal fibrosis. Overall design: Mice were fed either a high-fat diet or a normal diet to establish NAFLD mouse models and control groups. In the 11th week of feeding, unilateral ureteral obstruction (UUO) surgery was performed. After seven days, in the 12th week, the mice were euthanized, and kidneys from the ligated side (HU, WU) were collected for single-cell transcriptome sequencing.