Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Fujian Clinical Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China.
Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Fujian Clinical Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China.
Life Sci. 2022 Nov 1;308:120905. doi: 10.1016/j.lfs.2022.120905. Epub 2022 Aug 27.
Complement component 3a and its receptor (C3a/C3aR) and nucleotide-binding oligomerization domain-like receptor protein-3 (NLRP3) inflammasome are involved in the pathogenesis of renal interstitial fibrosis (RIF). However, the mechanisms have not been clearly illuminated. This study aimed to elucidate the roles of C3aR and the NLRP3 inflammasome involved in unilateral ureteral obstruction (UUO)-induced renal interstitial fibrosis.
UUO models were established using male C57BL/6 wild-type (WT) mice and age-matched C3aR-deficient mice. MCC950, an inhibitor of the NLRP3 inflammasome, was intraperitoneally injected in UUO mice. Blood samples were collected to quantify serum creatinine and urea. Kidney samples were collected for hematoxylin-eosin (HE), Masson, and immunohistochemistry staining, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay, and Western blotting.
Renal function, renal fibrosis, and renal inflammation in WT mice were aggravated with longer periods of UUO. C3aR deficiency improved renal function and attenuated renal fibrosis and the activation of the NLRP3 inflammasome in UUO mice. Renal function and renal fibrosis in UUO mice were attenuated after NLRP3 inflammasome inhibition; however, the expression of C3aR did not change.
Our data revealed that C3aR may aggravate RIF by regulating the activation of the NLRP3 inflammasome (particularly regulating inflammasome assembly) in renal tubular epithelial cells in the UUO model.
补体成分 3a 及其受体（C3a/C3aR）和核苷酸结合寡聚化结构域样受体蛋白 3（NLRP3）炎性小体参与了肾间质纤维化（RIF）的发病机制。然而，其机制尚未阐明。本研究旨在阐明 C3aR 和 NLRP3 炎性小体在单侧输尿管梗阻（UUO）诱导的肾间质纤维化中的作用。
使用雄性 C57BL/6 野生型（WT）小鼠和同龄 C3aR 缺陷型小鼠建立 UUO 模型。将 NLRP3 炎性小体抑制剂 MCC950 腹腔注射到 UUO 小鼠中。采集血样以定量检测血清肌酐和尿素。采集肾组织样本进行苏木精-伊红（HE）、Masson 和免疫组织化学染色、末端脱氧核苷酸转移酶 dUTP 缺口末端标记（TUNEL）检测和 Western blot 分析。
WT 小鼠的肾功能、肾纤维化和肾炎症随着 UUO 时间的延长而加重。C3aR 缺陷可改善 UUO 小鼠的肾功能，并减轻其肾纤维化和 NLRP3 炎性小体的激活。抑制 NLRP3 炎性小体可减轻 UUO 小鼠的肾功能和肾纤维化，但 C3aR 的表达并未改变。
我们的数据表明，在 UUO 模型中，C3aR 可能通过调节肾小管上皮细胞中 NLRP3 炎性小体的激活（特别是调节炎性小体组装）而加重 RIF。
