Oxidized high-density lipoprotein impairs the function of human renal proximal tubule epithelial cells through CD36

Abstract

Abstract. Unlike native high-density lipoprotein (HDL), oxidized HDL exerts adverse effects in a number of diseases, including chronic kidney disease (CKD); however, the mechanisms involved in this process remain unclear. In the present study, we investigated the effects of oxidized HDL on renal tubular cells, which play an important role in the progression of CKD. Human renal proximal tubule epithelial cells (HK-2) were cultured and stimulated with various concentrations of oxidized HDL in the absence or presence of CD36 siRNA. The results revealed that oxidized HDL enhanced the production of reactive oxygen species (ROS) and upregulated the expression of pro-inflammatory factors in the HK-2 cells in a dose-dependent manner. Incubation with oxidized HDL also increased the apoptosis of the HK-2 cells and reduced their migration ability in a dose-dependent manner. Src family kinase, mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) were activated following stimulation with oxidized HDL. All these effects mediated by oxidized HDL on HK-2 cells were markedly attenuated by transfection with with CD36 siRNA pior to stimulation with oxidized HDL. These findings suggest that oxidized HDL enhances the pro-inflammatory properties and impairs the function of HK-2 cells, mainly through the scavenger receptor, CD36, as well as through the Src, MAPK and NF-κB pathways.

Nox4 has a crucial role in uric acid-induced oxidative stress and apoptosis in renal tubular cells

“…The main MAPKs are P38, ERK1/2 and c-Jun N-terminal kinase 1/2, whose activity is stimulated by phosphorylation. The ROS-induced activation of MAPKs has been reported in several kidney diseases (26)(27)(28), while the association between UA and MAPKs has largely remained elusive; however, previous studies have indicated the participation of MAPKs in UA-induced tubular cell apoptosis (29,30). As the underlying mechanisms required further elucidation, the present study examined the phosphorylation of P38 and ERK1/2 and found them significantly activated following exposure to UA.…”

CD36 in chronic kidney disease: novel insights and therapeutic opportunities

“…131 Src family kinase was also activated in HK-2 cells following stimulation with Ox-HDL, and apoptosis was increased. 131…”

“…126 In human renal tubular (HK-2) and mesangial cells, binding of Ox-HDL to CD36 enhanced ROS production and upregulated the expression of proinflammatory factors via activation of p38/MAPK, extracellular-regulated kinase (ERK)/MAPK and NF-κB. 131 Src family kinase was also activated in HK-2 cells following stimulation with Ox-HDL, and apoptosis was increased. 131…”

“…CD36 is able to generate cell-specific responses to multiple ligands through the binding of context-specific binding partners (such as toll-like receptor 2 (TLR2), 147 TLR4, TLR6, 148 149 13 150 131 tetraspanin CD9, 151 integrin 152,153 and Na + /K + ATPase) and to activate NF-kB 154 , NLRP3 127 , PKC-NAPDH oxidase, 134 Src/Lyn/Fyn and MAPK kinases 131 , and TGF-β 22 signalling pathways (FIG. 2).…”

CD36 Gene Polymorphism and Susceptibility to Nephropathies

“…They showed that proteinuria results in accumulation of cholesterol in the kidney and that this is associated with upregulation of CD36, but also SRA-1 and ACAT1 and activation of SREBP-2 which can collectively raise tissue cholesterol and promote renal injury by facilitating the influx, synthesis and retention of cholesterol in the nephrotic kidney (18). The findings of a recent study suggest that oxidized HDL enhances the pro-inflammatory properties and impairs the function of Human renal proximal tubule epithelial cells which play an important role in the progression of CKD, mainly through the scavenger receptor, CD36, as well as through the Src, MAPK and NF-κB pathways (19). Finally, Kennedy et al…”