Tubular epithelial cell-to-macrophage communication forms a negative feedback loop via extracellular vesicle transfer to promote renal inflammation and apoptosis in diabetic nephropathy

Abstract

Background: Macrophage infiltration around lipotoxic tubular epithelial cells (TECs) is a hallmark of diabetic nephropathy (DN). However, how these two types of cells communicate remains obscure. We previously demonstrated that LRG1 was elevated in the process of kidney injury. Here, we demonstrated that macrophage-derived, LRG1-enriched extracellular vesicles (EVs) exacerbated DN. Methods: We induced an experimental T2DM mouse model with a HFD diet for four months. Renal primary epithelial cells and macrophage-derived EVs were isolated from T2D mice by differential ultracentrifugation. To investigate whether lipotoxic TEC-derived EV (EV e ) activate macrophages, mouse bone marrow-derived macrophages (BMDMs) were incubated with EV e . To investigate whether activated macrophage-derived EVs (EV m ) induce lipotoxic TEC apoptosis, EV m were cocultured with primary renal tubular epithelial cells. Subsequently, we evaluated the effect of LRG1 in EV e by investigating the apoptosis mechanism. Results: We demonstrated that incubation of primary TECs of DN or HK-2 mTECs with lysophosphatidyl choline (LPC) increased the release of EV e . Interestingly, TEC-derived EV e activated an inflammatory phenotype in macrophages and induced the release of macrophage-derived EV m . Furthermore, EV m could induce apoptosis in TECs injured by LPC. Importantly, we found that leucine-rich α-2-glycoprotein 1 (LRG1)-enriched EV e activated macrophages via a TGFβR1-dependent process and that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-enriched EV m induced apoptosis in injured TECs via a death receptor 5 (DR5)-dependent process. Conclusion: Our findings indicated a novel cell communication mechanism between tubular epithelial cells and macrophages in DN, which could be a potential therapeutic target.

Macrophage‐derived exosomal miR ‐195a‐5p impairs tubular epithelial cells mitochondria in acute kidney injury mice

“…29 The latest study indicated that TECs-Mφ communication, in diabetic nephropathy, forms a negative feedback loop via extracellular vesicle transfer to promote renal inflammation and apoptosis. 16 Similar to the findings, in our study we found that exosomes released from Mφ from AKI mice induced TECs injury.…”

“…13 Recent studies have also revealed that the cross-talks between Mφ and TECs played an important role in both repair/regeneration and disease progression. [14][15][16][17] However, the specific mechanism involved in Mφ-mediated kidney injury was not fully unclear.…”

Roles and crosstalks of macrophages in diabetic nephropathy

“…At the same time, high glucose stimulation is accompanied by the production of chemokines in renal tissue, which further increases the infiltration of macrophages ( 12 ). In addition, tubular epithelial cell-to-macrophage communication could form a negative feedback loop by extracellular vesicle (EV) to induce renal inflammation and apoptosis in DN ( 57 ). Leucine-rich α-2-glycoprotein 1(LRG1)-enriched extracellular vesicles derived from lipotoxic tubular epithelial cells activate M1 macrophages, which might be via a TGFβ receptor 1 (TGFβR1)-dependent manner ( 57 ).…”

“…In addition, tubular epithelial cell-to-macrophage communication could form a negative feedback loop by extracellular vesicle (EV) to induce renal inflammation and apoptosis in DN ( 57 ). Leucine-rich α-2-glycoprotein 1(LRG1)-enriched extracellular vesicles derived from lipotoxic tubular epithelial cells activate M1 macrophages, which might be via a TGFβ receptor 1 (TGFβR1)-dependent manner ( 57 ). Macrophages-derived extracellular vesicles containing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) lead to renal tubular epithelial cell apoptosis in a TRAIL-Death receptor 5 (DR5)-dependent manner ( 57 ).…”

Tubular epithelial cell-derived extracellular vesicles induce macrophage glycolysis by stabilizing HIF-1α in diabetic kidney disease

“…Recent studies have found that crosstalk between tubular epithelial cells and macrophages is key in regulating macrophage function (Kooten and Daha 2001;Bolisetty et al 2015;Masola et al 2018). Emerging evidence indicates that extracellular vesicles (EVs) mediate the transfer of information from tubular epithelial cells to macrophages (Lv et al 2018;Jia et al 2019;Jiang et al 2022). EVs are small membrane particles secreted by all types of cells that can carry messages via molecules such as nucleic acids and proteins to recipient cells (Colombo et al 2014).…”