대한신장학회

논문분류	춘계학술대회 초록집
제목	The role of autophagy in neutrophil extracellular trap (NET) formation in chronic uremia
저자	Jwa Kyung Kim, Mi Jin Park, Sun Ryoung Choi, Hyung Seok Lee, Sung Gyun Kim
출판정보	2018; 2018(1):
키워드	autophagy \| neutrophil extracellular traps \| uremia \| renal disorder \| endothelial dysfunction
초록	Objectives: Chronic uremia-related immune dysfunction could be a promising mechanism that links cardiovascular disease and renal disorders. In particular, dysregulated neutrophil function and increased neutrophil extracellular trap (NET) formation is recently regarded as an initiator of vascular inflammation. However, the mechanisms underlying neutrophil dysfunction in uremia remains uncertain. We investigate the association between NET formation and endothelial disorder in patients undergoing maintenance hemodialysis (MHD) and evaluated the role of autophagy in neutrophil dysfunction. Methods: The baseline serum extracellular DNA levels DNA-histone complex (cell-free nucleosome) were compared between MHD patients and healthy volunteer (HV). Then, neutrophils were isolated and stimulated with phorbol 12-myristate 13-acetate (PMA). The levels of NET formation were visualized with confocal microscopy and the presence of NETs were confirmed by directly measuring neutrophil elastase (NE) activities at baseline and after stimulation. Endothelial dysfunction was measured by flow-mediated dilatation (FMD) of brachial artery (Aloka Hitachi Prosound7). The autophagic status were evaluated and the effect of autophagy inhibition on NET formation was further investigated. Results: The median levels of serum extracellular DNA and cell-free nucleosome were significantly higher in MHD patients than HV (p<0.001). Also, neutrophils isolated from MHD patients showed an increased NE activity as well as higher NET formation than those from HV at baseline and after PMA stimulation. The increased NE activity showed a strong negative correlation with FMD(%, r=- 0.588, p<0.001). Similarly, the autophagic activities in MHD patients were significantly increased compared to that of HV. Interestingly, after treatment of 3MA or ammonium chloride, inhibitors of autophagy pathways at early and late stages, the levels of NET formation were markedly augmented especially after inhibition of autophagolysosomal degradation. Conclusions: Increased NET formation may be a causative factor of vascular dysfunction in uremic conditions. Activation of neutrophil autophagy could be an adaptive response to chronic uremic toxins as a protective manner.
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