Liu Bu-Hui, Chong Fee-Lan, Yuan Can-Can, Liu Ying-Lu, Yang Hai-Ming, Wang Wen-Wen, Fang Qi-Jun, Wu Wei, Wang Mei-Zi, Tu Yue, Wan Zi-Yue, Wan Yi-Gang, Wu Guo-Wen
Department of Traditional Chinese Medicine, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
Nephrology Division, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
Front Pharmacol. 2021 Jan 28;11:586725. doi: 10.3389/fphar.2020.586725. eCollection 2020.
Recently, chronic kidney disease (CKD)-mineral and bone disorder (MBD) has become one of common complications occurring in CKD patients. Therefore, development of a new treatment for CKD-MBD is very important in the clinic. In China, Fucoidan (FPS), a natural compound of has been frequently used to improve renal dysfunction in CKD. However, it remains elusive whether FPS can ameliorate CKD-MBD. FGF23-Klotho signaling axis is reported to be useful for regulating mineral and bone metabolic disorder in CKD-MBD. This study thereby aimed to clarify therapeutic effects of FPS in the CKD-MBD model rats and its underlying mechanisms and , compared to Calcitriol (CTR). All male rats were divided into four groups: Sham, CKD-MBD, FPS and CTR. The CKD-MBD rat models were induced by adenine administration and uninephrectomy, and received either FPS or CTR or vehicle after induction of renal injury for 21 days. The changes in parameters related to renal dysfunction and renal tubulointerstitial damage, calcium-phosphorus metabolic disorder and bone lesion were analyzed, respectively. Furthermore, at sacrifice, the kidneys and bone were isolated for histomorphometry, immunohistochemistry and Western blot. , the murine NRK-52E cells were used to investigate regulative actions of FPS or CTR on FGF23-Klotho signaling axis, ERK1/2-SGK1-NHERF-1-NaPi-2a pathway and Klotho deficiency. Using the modified CKD-MBD rat model and the cultured NRK-52E cells, we indicated that FPS and CTR alleviated renal dysfunction and renal tubulointerstitial damage, improved calcium-phosphorus metabolic disorder and bone lesion, and regulated FGF23-Klotho signaling axis and ERK1/2-SGK1-NHERF-1-NaPi-2a pathway in the kidney. In addition, using the shRNA-Klotho plasmid-transfected cells, we also detected, FPS accurately activated ERK1/2-SGK1-NHERF-1-NaPi-2a pathway through Klotho loss reversal. In this study, we emphatically demonstrated that FPS, a natural anti-renal dysfunction drug, similar to CTR, improves renal injury-related calcium-phosphorus metabolic disorder and bone abnormality in the CKD-MBD model rats. More importantly, we firstly found that beneficial effects and of FPS on phosphorus reabsorption are closely associated with regulation of FGF23-Klotho signaling axis and ERK1/2-SGK1-NHERF-1-NaPi-2a pathway in the kidney. This study provided pharmacological evidences that FPS directly contributes to the treatment of CKD-MBD.
近年来，慢性肾脏病（CKD）-矿物质和骨代谢紊乱（MBD）已成为CKD患者常见的并发症之一。因此，开发针对CKD-MBD的新治疗方法在临床上非常重要。在中国，褐藻糖胶（FPS），一种天然化合物，已被频繁用于改善CKD患者的肾功能障碍。然而，FPS是否能改善CKD-MBD仍不清楚。据报道，FGF23-klotho信号轴有助于调节CKD-MBD中的矿物质和骨代谢紊乱。因此，本研究旨在阐明FPS对CKD-MBD模型大鼠的治疗作用及其潜在机制，并与骨化三醇（CTR）进行比较。所有雄性大鼠分为四组：假手术组、CKD-MBD组、FPS组和CTR组。通过给予腺嘌呤和单侧肾切除术诱导CKD-MBD大鼠模型，并在肾损伤诱导21天后给予FPS或CTR或赋形剂。分别分析与肾功能障碍、肾小管间质损伤、钙磷代谢紊乱和骨病变相关参数的变化。此外，在处死时，分离肾脏和骨骼进行组织形态计量学、免疫组织化学和蛋白质印迹分析。此外，使用小鼠NRK-52E细胞研究FPS或CTR对FGF23-Klotho信号轴、ERK1/2-SGK1-NHERF-1-NaPi-2a通路和Klotho缺乏的调节作用。利用改良的CKD-MBD大鼠模型和培养的NRK-52E细胞，我们发现FPS和CTR均可减轻肾功能障碍和肾小管间质损伤，改善钙磷代谢紊乱和骨病变，并调节肾脏中的FGF23-Klotho信号轴和ERK1/2-SGK1-NHERF-1-NaPi-2a通路。此外，使用shRNA-Klotho质粒转染细胞，我们还检测到，FPS通过逆转Klotho缺失准确激活ERK1/2-SGK1-NHERF-1-NaPi-2a通路。在本研究中，我们着重证明了FPS，一种天然的抗肾功能障碍药物，与CTR类似，可改善CKD-MBD模型大鼠中与肾损伤相关的钙磷代谢紊乱和骨异常。更重要的是，我们首次发现FPS对磷重吸收的有益作用与肾脏中FGF23-Klotho信号轴和ERK1/2-SGK1-NHERF-1-NaPi-2a通路的调节密切相关。本研究提供了药理学证据，证明FPS对CKD-MBD的治疗有直接作用。
