Targeting Macrophage Lp-PLA2 to Attenuate Kidney Dysfunction in Diabetic Kidney Disease

Background: Modern lifestyles have driven a surge in diabetes prevalence, thereby elevating the risk of diabetic nephropathy. The immune-inflammatory response also plays a critical role in the kidney damage resulting from hyperglycaemia. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a reliable inflammatory marker for cardiovascular risk, and recent research has linked it to diabetic microangiopathy. However, its role and regulatory mechanisms in diabetic kidney disease (DKD) require further investigation. Methods: We utilized the scPagwas method to integrate single-cell sequencing and GWAS data. This enabled us to identify the kidney cell type most relevant to urinary protein secretion in early-stage DKD mice and screen for potential drug targets within its differentially expressed genes. Utilizing different DKD mouse models, we investigated the renal expression patterns of potential drug target genes. Additionally, after administering drug target inhibitors to DKD mice, we employed RNA and lipidomics sequencing to screen for altered downstream targets and associated pathway modifications. We established a Transwell co-culture system with tubular and macrophage cells to investigate the mechanism by which the target gene influences macrophage-mediated damage to tubular cells. Finally, a Phase I clinical trial was conducted in 13 DKD subjects for drugs targeting these genes. Results: A screen in our study pinpointed macrophage-expressed Pla2g7 as a potential drug target for DKD. Subsequently, administering Lp-PLA2 inhibitors to DKD mice led to a significant amelioration of renal inflammatory expansion and lipid deposition. Further in vitro analyses demonstrated that lysophosphatidic acid (LPA), an end product of oxidized lipids generated by Lp-PLA2 catabolism, activates macrophage LPAR1, a critical pathway for triggering inflammatory enlargement and tubular injury. Notably, Lp-PLA2 administration significantly reduced urinary protein levels in DKD patients. Collectively, these studies suggest that Lp-PLA2 inhibition reduces renal LPAR1 activation, contributing to the amelioration of renal dysfunction. Conclusion: Our research on Lp-PLA2's role in macrophage activation and tubular damage during diabetic kidney injury has identified promising new therapeutic strategies for DKD. Funding: Commercial Support - Shanghai SIMR Biotechnology Co., Government Support – Non-U.S.