Division of Nephrology, Kidney Institute of PLA, Changzheng Hospital, Second Military Medical University, Shanghai, China.
Adv Exp Med Biol. 2019;1165:81-100. doi: 10.1007/978-981-13-8871-2_5.
Polycystic kidney disease (PKD) is a common genetic disorder characterized by formations of numerous cysts in kidneys and most caused by PKD1 or PKD2 mutations in autosomal dominant polycystic kidney disease (ADPKD). The interstitial inflammation and fibrosis is one of the major pathological changes in polycystic kidney tissues with an accumulation of inflammatory cells, chemokines, and cytokines. The immune response is observed across different stages and occurs prior to or coincident with cyst formation in ADPKD. Evidence for inflammation as an important contributor to cyst growth and fibrosis includes increased interstitial macrophages, upregulated expressions of pro-inflammatory cytokines, activated complement system, and activated pathways including NF-κB and JAK-STAT signaling in polycystic kidney tissues. Inflammatory cells are responsible for overproduction of several pro-fibrotic growth factors which promote renal fibrosis in ADPKD. These growth factors trigger epithelial mesenchymal transition and myofibroblast/fibrocyte activation, which stimulate the expansion of extracellular matrix (ECM) including collagen I, III, IV, V, and fibronectin, leading to renal fibrosis and reduced renal function. Besides, there are imbalanced ECM turnover regulators which lead to the increased ECM production and inadequate degradation in polycystic kidney tissues. Several fibrosis associated signaling pathways, such as TGFβ-SMAD, Wnt, and periostin-integrin-linked kinase are also activated in polycystic kidney tissues. Although the effective anti-fibrotic treatments are limited at the present time, slowing the cyst expansion and fibrosis development is very important for prolonging life span and improving the palliative care of ADPKD patients. The inhibition of pro-fibrotic cytokines involved in fibrosis might be a new therapeutic strategy for ADPKD in the future.
多囊肾病（PKD）是一种常见的遗传性疾病，其特征是肾脏中形成许多囊肿，大多数常染色体显性多囊肾病（ADPKD）是由 PKD1 或 PKD2 突变引起的。间质炎症和纤维化是多囊肾病组织的主要病理变化之一，其特征是炎症细胞、趋化因子和细胞因子的积累。免疫反应发生在不同的阶段，在 ADPKD 中囊肿形成之前或同时发生。炎症作为促进囊肿生长和纤维化的重要因素的证据包括间质巨噬细胞增加、促炎细胞因子表达上调、补体系统激活以及 NF-κB 和 JAK-STAT 信号通路激活。炎症细胞负责过度产生几种促纤维化生长因子，这些因子促进 ADPKD 中的肾纤维化。这些生长因子引发上皮间充质转化和肌成纤维细胞/成纤维细胞激活，刺激细胞外基质（ECM）的扩张，包括胶原 I、III、IV、V 和纤维连接蛋白，导致肾纤维化和肾功能降低。此外，还有 ECM 周转调节剂失衡，导致多囊肾病组织中 ECM 产生增加和降解不足。几种纤维化相关信号通路，如 TGFβ-SMAD、Wnt 和periostin-integrin-linked kinase，也在多囊肾病组织中被激活。尽管目前有效的抗纤维化治疗方法有限，但减缓囊肿扩张和纤维化发展对于延长 ADPKD 患者的寿命和改善姑息治疗非常重要。抑制参与纤维化的促纤维化细胞因子可能是未来 ADPKD 的一种新的治疗策略。
