Immune Cell Infiltration and Kynurenine Pathway Activation Define Early Injury and Progression in Diabetic Nephropathy

Diabetic nephropathy (DN), a major complication of diabetes, is the leading cause of end-stage kidney disease; however, a comprehensive understanding of the dynamic immune-inflammatory changes during DN progression remains limited. We integrated single-cell RNA sequencing, in vivo diabetic models, and clinical samples from type 2 diabetes (T2D) patients to investigate cellular and molecular alterations across different stages of DN. Our results revealed a significant increase in immune cell infiltration in early DN in two mouse models. Notably, CCL4⁺ myeloid-derived suppressor cells (MDSCs) with a pro-inflammatory phenotype emerged as the predominant infiltrating immune population, with S100A9 highly expressed in these cells, serving as early molecular indicators. Compared to healthy individuals, T2D patients exhibited elevated levels of circulating MDSCs. Long non-coding RNA MALAT1 was identified as a key factor in maintaining MDSC function. In late DN, elevated expression of CD9 and TREM2 in kidney macrophages suggested a role for lipid-associated macrophages in DN progression. Concurrently, endothelial cell reprogramming characterized by GPX3 and SPP1 expression was observed during DN advancement. Furthermore, kynureninase, a key enzyme in the kynurenine pathway (KP), was upregulated in proximal tubule injury during early DN. The metabolites of KP including kynurenine, 3-hydroxykynurenine, and quinolinic acid were associated with enhanced induction of MDSCs in mice, as well as with adverse renal outcomes in T2D patients. Collectively, this study delineates the dynamic immune-inflammatory landscape of DN, uncovers key molecular players across disease stages, and provides novel insights into potential diagnostic markers and therapeutic targets.