Depletion of intrinsic renal macrophages with moderate-to-high expression of CD163, MRC1, PTH2R, PDE4D, and CUBN in regulating podocyte injury in diabetic nephropathy: a single-cell RNA sequencing analysis.

Background: Diabetic nephropathy (DN), a severe complication of diabetes, is characterized by glomerular and tubular damage, which often leads to end-stage renal disease (ESRD). The role of renal macrophages (Mφs), particularly their phenotypic plasticity and function in DN, remains poorly understood. This study investigated the key factors influencing Mφ polarization and their impact on podocyte (PODO) injury in DN.

Methods: Single-nuclear RNA sequencing (snRNA-seq) data from DN and control (CON) kidney samples were analyzed for cell clustering, differential expression, and cell communication. Mφs were identified and categorized based on their gene expression profiles. The proportions and functions of different Mφ phenotypes were compared between DN and CON samples, with a focus on their interaction with PODOs.

Results: A subset of Mφs, characterized by high expression of CD163, MRC1, PTH2R, PDE4D, and CUBN, was significantly depleted in DN as compared to in CON samples. This depletion was associated with the overexpression of AHR and underexpression of IGF1R, inhibiting the differentiation of these protective Mφs. The remaining Mφs in the DN samples exhibited altered functions, particularly in regulating oxidative stress and tight junctions. Their interaction with PODOs through ligands including NRG3 and THBS1 suggested a role in promoting PODO dysfunction and apoptosis and their contribution to the progression of DN.

Conclusions: The depletion of Mφs with a moderate-to-high expression of CD163, MRC1, PTH2R, PDE4D, and CUBN in patients with DN leads to enhanced PODO injury and apoptosis, highlighting a potential therapeutic target for mitigating DN progression. Further research into the mechanisms governing Mφ-PODO interactions could provide insights into novel treatment strategies for DN.