Desmosterol-driven atypical macrophage polarization regulates podocyte dynamics in diabetic nephropathy

Diabetic nephropathy (DN) stands as a leading diabetes complication, with macrophages intricately involved in its evolution. While glucose metabolism's impact on macrophage activity is well-established, cholesterol metabolism's contributions remain less explored. Our study seeks to elucidate this association.

Methods and Results: Gene expression analysis of monocytes from the blood of both normal and diabetic patients was conducted using public databases, showing that cholesterol metabolism pathways, especially Bloch and Kandutsch-Russell, were more altered in diabetic monocytes/macrophages than glucose-responsive pathways. When bone marrow-derived macrophages (BMDMs) were subjected to desmosterol, they exhibited an unconventional polarization. These BMDMs displayed heightened levels of both M1-related pro-inflammatory cytokines and M2-linked anti-inflammatory factors. Further, in co-culture, desmosterol-conditioned BMDMs paralleled M2 macrophages in augmenting Ki-67 + podocyte populations while mimicking M1 macrophages in elevating TUNEL + apoptotic podocytes. Comparable outcomes on podocytes were obtained using conditioned media from the respective BMDMs.

Our data underscores the pivotal role of cholesterol metabolism, particularly via desmosterol, in steering macrophages toward an unconventional polarization marked by both inflammatory and regulatory traits. Such unique macrophage behavior concurrently impacts podocyte proliferation and apoptosis, shedding fresh light on DN pathogenesis and hinting at potential therapeutic interventions.