Abstract
Tubulointerstitial inflammation plays a key role in the pathogenesis of diabetic nephropathy (DN). Interleukin-1β (IL-1β) is the key proinflammatory cytokine associated with tubulointerstitial inflammation. The NLRP3 inflammasome regulates IL-1β activation and secretion. Reactive oxygen species (ROS) represents the main mediator of NLRP3 inflammasome activation. We previously reported that CD36, a class B scavenger receptor, mediates ROS production in DN. Here, we determined whether CD36 is involved in NLRP3 inflammasome activation and explored the underlying mechanisms. We observed that high glucose induced-NLRP3 inflammasome activation mediate IL-1β secretion, caspase-1 activation, and apoptosis in HK-2 cells. In addition, the levels of CD36, NLRP3, and IL-1β expression (protein and mRNA) were all significantly increased under high glucose conditions. CD36 knockdown resulted in decreased NLRP3 activation and IL-1β secretion. CD36 knockdown or the addition of MitoTempo significantly inhibited ROS production in HK-2 cells. CD36 overexpression enhanced NLRP3 activation, which was reduced by MitoTempo. High glucose levels induced a change in the metabolism of HK-2 cells from fatty acid oxidation (FAO) to glycolysis, which promoted mitochondrial ROS (mtROS) production after 72 h. CD36 knockdown increased the level of AMP-activated protein kinase (AMPK) activity and mitochondrial FAO, which was accompanied by the inhibition of NLRP3 and IL-1β. The in vivo experimental results indicate that an inhibition of CD36 could protect diabetic db/db mice from tubulointerstitial inflammation and tubular epithelial cell apoptosis. CD36 mediates mtROS production and NLRP3 inflammasome activation in db/db mice. CD36 inhibition upregulated the level of FAO-related enzymes and AMPK activity in db/db mice. These results suggest that NLRP3 inflammasome activation is mediated by CD36 in renal tubular epithelial cells in DN, which suppresses mitochondrial FAO and stimulates mtROS production.
Highlights
Diabetic nephropathy (DN) is one of the most severe chronic microvascular complications of diabetes mellitus, which currently represents the leading cause of end-stage renal failure worldwide[1]
The level of apoptosis-associated Bax/ Bcl-2 ratio and cleaved caspase-3 were markedly increased in db/db mice group compared to the db/m group, which was reduced in CD36-knockdown mice (Fig. 6H).These findings indicate that CD36 expression is associated with the apoptotic events of proximal tubular cells, suggesting that CD36 may play a role in renal tubular injury in diabetic kidneys
In the present study, we reported both ex vivo and in vivo data showing that CD36 stimulates NLRP3 inflammasome activation through mitochondrial ROS (mtROS) in renal tubular epithelial cells in DN
Summary
Diabetic nephropathy (DN) is one of the most severe chronic microvascular complications of diabetes mellitus, which currently represents the leading cause of end-stage renal failure worldwide[1]. Previous research suggests that tubulointerstitial inflammation plays an independent role in promoting the pathogenesis of renal function in DN; Official journal of the Cell Death Differentiation Association. In rat models of diabetes and cultured renal cells, ROS has been shown to activate the NLRP3 inflammasome by activating thioredoxin-interacting protein[11]. The transcription factor, NF-κB, which can be activated by ROS, has been shown to be involved in NLRP3 inflammasome activation in DN12. Another study found that silencing the Nrf[2] gene (a transcription factor that mediates anti-oxidant genes) in podocytes increased the activation of the NLRP3 inflammasome[13]. The literature indicates that ROS appear to play an important role in HG-mediated activation of the NLRP3 inflammasome in DN
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