Infiltrating macrophages in diabetic nephropathy promote podocytes apoptosis via TNF-α-ROS-p38MAPK pathway

Abstract

Macrophage infiltration has been linked to the pathogenesis of diabetic nephropathy (DN). However, how infiltrating macrophages affect the progression of DN is unknown. Although infiltrating macrophages produce pro-inflammatory mediators and induce apoptosis in a variety of target cells, there are no studies in podocytes. Therefore, we tested the contribution of macrophages to podocytes apoptosis in DN. in vivo experiments showed that apoptosis in podocytes was increased in streptozocin (STZ)-induced diabetic rats compared with control rats and that this apoptosis was accompanied by increased macrophages infiltration in the kidney. Then, we established a co-culture system to study the interaction between macrophages and podocytes in the absence or presence of high glucose. Macrophages did not trigger podocytes apoptosis when they were co-cultured in the absence of high glucose in a transwell co-culture system. Additionally, although podocyte apoptosis was increased after high glucose stimulation, there was a further enhancement of podocyte apoptosis when podocytes were co-cultured with macrophages in the presence of high glucose compared with podocytes cultured alone in high glucose. Mechanistically, we found that macrophages were activated when they were exposed to high glucose, displaying pro-inflammatory M1 polarization. Furthermore, conditioned media (CM) from such high glucose-activated M1 macrophages (HG-CM) trigged podocytes apoptosis in a reactive oxygen species (ROS)-p38mitogen-activated protein kinases (p38MAPK) dependent manner, which was abolished by either a ROS inhibitor (Tempo) or a p38MAPK inhibitor (SB203580). Finally, we identified tumor necrosis factor (TNF-α) as a key mediator of high glucose-activated macrophages to induce podocytes apoptosis because an anti-TNF-α neutralizing antibody blunted the apoptotic response, excess ROS generation and p38MPAK activation in podocytes induced by HG-CM. Moreover, addition of recombinant TNF-α similarly resulted in podocytes apoptosis. In summary, the TNF-α that was released by high glucose-activated macrophages promoted podocytes apoptosis via ROS-p38MAPK pathway. Blockade of TNF-α secretion from high glucose activated macrophages and ROS-p38MAPK pathway might be effective therapeutic options to limit podocytes apoptosis and delay the progression of diabetic nephropathy.

Genetic or pharmacologic inhibition of EGFR ameliorates sepsis-induced AKI

“…In support of this possibility, Wa-2 mice showed less cell apoptosis in renal cortex and medulla after CLP induced AKI (Figure 10 ). In addition, although EGFR usually mediates cell proliferation and anti-apoptotic effects, our current study showed that activation of EGFR induced apoptosis, the possibility explanation is that activation of EGFR significantly increased proinflammatory cytokines production(Figure 4C & 4D ), including TNF-α and TGF-β, which can promote kidney cell apoptosis [ 32 , 33 ]. Furthermore, NLRP3 plays a crucial role in innate immunity and inflammation, which has been reported in CLP induced AKI [ 34 ].…”

Astragaloside IV/lncRNA-TUG1/TRAF5 signaling pathway participates in podocyte apoptosis of diabetic nephropathy rats

“… 18 Numerous studies have shown that podocyte injury occurred in DN through different signaling pathways, such as lncRNA LINC01619/miR-27a/FOXO1, TGFβ1-PI3K/AKT, TNF-α-ROS-p38MAPK pathways, etc. 19 – 21 When podocyte injury occurs, the renal glomerular filtration barrier cannot be maintained, which leads to proteinuria. 22 The present study explored a new pathway from AS-IV to TRAF5 in reducing podocytes apoptosis for the treatment of DN.…”

The mechanism of mulberry leaves against renal tubular interstitial fibrosis through ERK1/2 signaling pathway was predicted by network pharmacology and validated in human tubular epithelial cells

“…Recent studies have painted an interesting picture on the emerging role of oxidative stress, whereby the excessive generation of ROS is associated with the structural and functional damage of various organs. Then, intracellular ROS generation has been reported to a potential mediator, which played an essential role in the induction of EMT and contributed to apoptosis in the progression of DN (Guo et al, ; Sun et al, ; Xu et al, ). Consistent with these studies, it has been confirmed in present study that high glucose conditions increased ROS generation.…”