Exploring macrophage heterogeneity in IgA nephropathy: Mechanisms of renal impairment and current therapeutic targets

The lack of understanding of the mechanism of renal injury in IgA nephropathy (IgAN) hinders the development of personalized treatment plans and targeted therapies. Improved insight into the cause of renal dysfunction in IgAN is necessary to enhance the effectiveness of strategies for slowing the progression of the disease. This study examined single cell RNA sequencing (scRNA seq) and bulk-RNA seq data and found that the gene expression of renal intrinsic cells (RIC) was significantly changed in patients with renal impairment, with a primary focus on energy metabolism. We discovered a clear metabolic reprogramming of RIC during renal function impairment (RF) using the 'scMetabolism' package, which manifested as a weakening of oxidative phosphorylation, alterations in fatty acid metabolism, and changes in glycolysis. Cellular communication analysis revealed that communication between macrophages (Ma) and RIC became more active and impacted cell function through the ligand-receptor-transcription factor (L-R-TF) axis in patients with RF. Our studies showed a notable upsurge in the expression of gene CLU and the infiltration of CLU⁺ Ma in patients with RF. CLU is a multifunctional protein, extensively involved in processes such as cell apoptosis and immune responses. Data obtained from the Nephroseq V5 database and multiplex immunohistochemistry (mIHC) were used to validate the findings, which were found to be robustly correlated with estimated glomerular filtration rate (eGFR) of the IgAN patients, as demonstrated by linear regression (LR). This study provides new insights into the cellular and molecular changes that occur in IgAN during renal impairment, revealing that elevated expression of CLU and CLU⁺ Ma percolation are common features in patients with RF. These findings offer potential targets and strategies for personalized management and targeted therapy of IgAN.