Toll-like receptor-4 deficiency alleviates chronic intermittent hypoxia-induced renal injury, inflammation, and fibrosis

作者：Zhang, Yan; Su, Xiaoli^*; Zou, Fangfang; Xu, Tengjuan; Pan, Pinhua; Hu, Chengping

来源：Sleep and Breathing, 2019, 23(2): 503-513.

DOI：10.1007/s11325-018-1704-9

• Obstructive sleep apnea
• Toll-like receptor 4
• Chronic intermittent hypoxia
• Renal damage

Background Obstructive sleep apnea (OSA)-associated chronic kidney disease is mainly caused by chronic intermittent hypoxia (CIH) triggered renal damage. This study aims to investigate the role of toll-like receptor-4 (TLR4) in underlying mechanism involved chronic intermittent hypoxia (CIH)-induced renal damage. @@@ Methods C57BL/6J mice with normal TLR4 (TLR4 WT) or deficient TLR4 (TLR4 KO) were divided into four groups and exposed to normal air (NA) and CIH: TLR4 WT + NA, TLR4 KO + NA, TLR4 WT + CIH, and TLR4 KO + CIH. CIH lasted for 8h/day and 7days/week for 6weeks. Renal injury and inflammation were evaluated by histology and ELISA. Renal tubular apoptosis, macrophages, and fibroblasts recruitment were determined by TUNEL assay, immunofluorescence, and western blot. @@@ Results In response to CIH, TLR4 deficiency alleviated renal histological injury, renal dysfunction, and fibrosis. TLR4 deficiency ameliorated renal dysserum BUN and creatinine) and tubular endothelial apoptosis determined by immunofluorescence staining of CD31 and TUNEL, and western blot of apoptotic protein (caspase-3, c-caspase-3, and Bax/Bcl-2 ratio). Furthermore, we also found TLR4 deficiency abrogated CIH-induced macrophages (CD68) and fibroblasts (-SMA) recruitment, further reducing expression of extra-cellular matrix protein (collagen I and collagen IV) and inflammatory cytokines release (IL-6, TNF-, and MCP-1). Finally, we used immunohistochemistry to demonstrate that TLR4 deficiency attenuated increased expression of MyD88 and NF-kB p65 after CIH treatment. @@@ Conclusions Our data suggest that TLR4 plays a vital role in CIH-induced renal injury, inflammation and fibrosis, and inhibition of TLR4 probably provides a therapeutic potential for CIH-induced kidney damage.

• 出版日期2019-6
• 单位中南大学