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Войти в исследования Mutation research · 2026
Deubiquitinase USP10 regulates angiotensin II-induced renal fibrosis by modulating the expression of TLR4.
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Wang Rong, Shen Yanjun, Shi Jiaqi, Huang Huaxing, Feng Sujuan, Fang Xingxing, Gu Xiameng, Yu Yang
Аннотация
BACKGROUND: Diabetic kidney disease (DKD) is one of the main causes of chronic kidney disease (CKD). There is evidence suggesting that the upregulation of Toll-like receptor 4 (TLR4) can exacerbate the progression of diabetic nephropathy. In addition, the expression of the deubiquitinating enzyme USP10 is upregulated in the kidney tissues of patients with CKD. However, the specific relationship between USP10 and TLR4 has not been clearly elucidated.
METHODS: Human renal mesangial cells (HRMCs) were induced with angiotensin II (Ang II) to mimic the pathological features of renal fibrosis. The mRNA and protein levels of TLR4 and USP10 were monitored by RT-qPCR and western blot. Then, cell proliferation behavior was visualized by EdU. Meanwhile, the levels of ROS, GSH, MDA, SOD, IL-6, and TNF-α in HRMCs were measured with the corresponding kits. The UbiBrowser website was subsequently applied to predict TLR4 binding to USP10. Furthermore, the binding of USP10 to TLR4 and its deubiquitination modification of TLR4 were validated by IP, IB and, Co-IP techniques. The protein stability of TLR4 was examined in the presence of cycloheximide (CHX).
RESULTS: TLR4 was highly expressed in DKD kidney tissues and AngII-induced HRMCs, and silencing TLR4 could effectively prevent the abnormal proliferation, oxidative stress, inflammation, and fibrosis process of HRMCs caused by AngII. Additionally, USP10 expression was upregulated in DKD kidney tissues and AngII-induced HRMCs, which mediated TLR4 deubiquitination to stabilize its protein expression. Most importantly, overexpression of TLR4 reversed the effect of USP10 silencing on AngII-induced HRMCs.
CONCLUSION: This study elucidated that USP10 facilitated the deubiquitination of TLR4 within AngII-stimulated HRMCs, thereby sustaining elevated levels of TLR4 protein. This mechanism not only incited aberrant proliferation of HRMCs but also triggered oxidative stress and inflammatory responses, ultimately expediting the progression of renal fibrosis.
METHODS: Human renal mesangial cells (HRMCs) were induced with angiotensin II (Ang II) to mimic the pathological features of renal fibrosis. The mRNA and protein levels of TLR4 and USP10 were monitored by RT-qPCR and western blot. Then, cell proliferation behavior was visualized by EdU. Meanwhile, the levels of ROS, GSH, MDA, SOD, IL-6, and TNF-α in HRMCs were measured with the corresponding kits. The UbiBrowser website was subsequently applied to predict TLR4 binding to USP10. Furthermore, the binding of USP10 to TLR4 and its deubiquitination modification of TLR4 were validated by IP, IB and, Co-IP techniques. The protein stability of TLR4 was examined in the presence of cycloheximide (CHX).
RESULTS: TLR4 was highly expressed in DKD kidney tissues and AngII-induced HRMCs, and silencing TLR4 could effectively prevent the abnormal proliferation, oxidative stress, inflammation, and fibrosis process of HRMCs caused by AngII. Additionally, USP10 expression was upregulated in DKD kidney tissues and AngII-induced HRMCs, which mediated TLR4 deubiquitination to stabilize its protein expression. Most importantly, overexpression of TLR4 reversed the effect of USP10 silencing on AngII-induced HRMCs.
CONCLUSION: This study elucidated that USP10 facilitated the deubiquitination of TLR4 within AngII-stimulated HRMCs, thereby sustaining elevated levels of TLR4 protein. This mechanism not only incited aberrant proliferation of HRMCs but also triggered oxidative stress and inflammatory responses, ultimately expediting the progression of renal fibrosis.