Li Jiaxiao, Chen Junzhe, Lan Hui-Yao, Tang Ying
Department of Nephrology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China.
Departments of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, and Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Hong Kong, China.
Kidney Dis (Basel). 2022 Dec 14;9(2):73-81. doi: 10.1159/000528693. eCollection 2023 Apr.
C-reactive protein (CRP) is an acute-phase protein and has been found to be a risk factor for acute kidney injury (AKI) and chronic kidney diseases (CKD). However, the role and mechanisms of CRP in AKI and CKD remain largely unclear.
Clinically, elevated serum CRP is a risk factor or biomarker for patients with AKI and CKD. Interestingly, in critically ill COVID-19 patients, increased serum CRP is also associated with the development of AKI. Functionally, studies using human CRP transgenic mouse models find that CRP is pathogenic and can function as a mediator for AKI and CKD as mice overexpressing human CRP promote AKI and CKD. Mechanistically, CRP can promote AKI and CKD via NF-κB and Smad3-dependent mechanisms. We found that CRP can activate Smad3 signaling directly and cause AKI via the Smad3-p27-dependent G1 cell cycle arrest mechanism. Thus, targeting CRP-Smad3 signaling with a neutralizing antibody or Smad3 inhibitor can inhibit AKI.
CRP acts not only as a biomarker but also as a mediator for AKI and CKD. CRP can activate Smad3 to induce cell death and cause progressive renal fibrosis. Thus, targeting CRP-Smad3 signaling may represent a promising therapy for AKI and CKD.
C反应蛋白（CRP）是一种急性期蛋白，已被发现是急性肾损伤（AKI）和慢性肾脏病（CKD）的危险因素。然而，CRP在AKI和CKD中的作用及机制仍不清楚。
临床上，血清CRP升高是AKI和CKD患者的危险因素或生物标志物。有趣的是，在危重症COVID-19患者中，血清CRP升高也与AKI的发生有关。在功能上，使用人CRP转基因小鼠模型的研究发现，CRP具有致病性，可作为AKI和CKD的介质，因为过表达人CRP的小鼠会促进AKI和CKD。在机制上，CRP可通过NF-κB和Smad3依赖性机制促进AKI和CKD。我们发现，CRP可直接激活Smad3信号，并通过Smad3-p27依赖性G1细胞周期阻滞机制导致AKI。因此，用中和抗体或Smad3抑制剂靶向CRP-Smad3信号可抑制AKI。
CRP不仅作为生物标志物，还作为AKI和CKD的介质。CRP可激活Smad3诱导细胞死亡并导致进行性肾纤维化。因此，靶向CRP-Smad3信号可能是AKI和CKD的一种有前景的治疗方法。
