Chrysophanol, a main anthraquinone from Rheum palmatum L. (rhubarb) , protects against renal fibrosis by suppressing NKD2/NF-κB pathway

被引:34
作者
Gu, Mingjia [1 ]
Zhou, Yufeng [1 ]
Liao, Naikai [2 ]
Wei, Qingxue [1 ]
Bai, Zijun [3 ,4 ]
Bao, Neng [5 ]
Zhu, Ying [1 ]
Zhang, Hang [1 ]
Gao, Leiping [1 ]
Cheng, Xiaolan [3 ,4 ]
机构
[1] Nanjing Univ Chinese Med, Dept Nephrol, Changshu Hosp, 6 Huanghe Rd, Changshu 215500, Jiangsu, Peoples R China
[2] Guangxi Med Univ, Dept Urol, Affiliated Hosp 1, 6 Shuangyong Rd, Nanning, Guangxi, Peoples R China
[3] Nanjing Univ Chinese Med, Sch Chinese Med, 138 Xianlin Ave, Nanjing 210023, Jiangsu, Peoples R China
[4] Nanjing Univ Chinese Med, Sch Integrated Chinese & Western Med, 138 Xianlin Ave, Nanjing 210023, Jiangsu, Peoples R China
[5] Affiliated Hosp Jiangnan Univ, Dept Nephrol, 1000 Hefeng Rd, Wuxi 214000, Jiangsu, Peoples R China
关键词
Chronic kidney disease; Rhubarb; Chrysophanol; Renal fibrosis; NKD2; NF-kappa B; FIBRONECTIN; MECHANISMS; HETEROZYGOSITY; RECEPTOR; GROWTH; NKD2;
D O I
10.1016/j.phymed.2022.154381
中图分类号
Q94 [植物学];
学科分类号
071001 ;
摘要
Purpose: Chronic kidney disease (CKD), characterized as renal dysfunction and multi-system damage, has become a serious public health problem with high prevalence and mortality. Rheum palmatum L. (rhubarb) is one of the most widely used Chinese herb with renal protective activity. However, the active components and underlying mechanisms of rhubarb remain unknown. In this work, we tried to explore the pharmacological mechanism of chrysophanol, a main anthraquinone from rhubarb, against CKD by in vivo and in vitro models.Study design: The therapeutic effect of chrysophanol and its underlying mechanism were investigated using CKD mouse model induced by unilateral ureteral occlusion (UUO), and human kidney 2 (HK-2) cells stimulated by TGF-81 in vivo. Methods: The impact of chrysophanol on renal function, inflammation, fibrosis of CKD mice were evaluated. Then, the protein expressions of FN1, collagen alphaI, alpha-SMA, NF-Kappa B and naked keratinocyte homolog 2 (NKD2) were investigated. In vitro studies, the inhibition on inflammation and fibrogenesis by chrysophanol was further validated in TGF-81-stimulated HK2 cells, and the regulation of chrysophanol on NKD2/NF-Kappa B pathway was analyzed. Moreover, NKD2 was overexpressed in HK-2 cells to confirm the role of NKD2/NF-Kappa B pathway in chrysophanol-mediated efficacy. Finally, the binding mode of chrysophanol with NKD2 was studied using in silico molecular docking and microscale thermophoresis (MST) assay. Results: Chrysophanol could significantly improve the kidney dysfunction, alleviate renal pathology, and reverse the elevated levels of renal fibrosis markers such as FN1, collagen alphaI and alpha-SMA. Furthermore, chrysophanol effectively inhibited TNF-alpha, IL-6, and IL-18 production, and suppressed NF-Kappa B activation and NKD2 expression. The findings of in vitro study were consistent with those of animal expriment. Using NKD2-overexpressing HK-2 cells, we also demonstrated that overexpression of NKD2 significantly compromised the anti-fibrotic effects of chrysophanol. In addition, molecular docking and MST analysis revealed that NKD2 was a direct target of chrysophanol. Conclusion: Together, our work demonstrated for the first time that chrysophanol could effectively ameliorate renal fibrosis by inhibiting NKD2/NF-Kappa B pathway. Chrysophanol can potentially prevent CKD by suppressing renal NKD2 expression directly.
引用
收藏
页数:12
相关论文
共 53 条
[1]  
Anavekar NS, 2004, NEW ENGL J MED, V351, P1285, DOI 10.1056/NEJMoa041365
[2]   IMMUNOLOCALIZATION OF TENASCIN AND CELLULAR FIBRONECTINS IN DIVERSE GLOMERULOPATHIES [J].
ASSAD, L ;
SCHWARTZ, MM ;
VIRTANEN, I ;
GOULD, VE .
VIRCHOWS ARCHIV B-CELL PATHOLOGY INCLUDING MOLECULAR PATHOLOGY, 1993, 63 (05) :307-316
[3]   A Water-Soluble Antibiotic in Rhubarb Stalk Shows an Unusual Pattern of Multiple Zones of Inhibition and Preferentially Kills Slow-Growing Bacteria [J].
Bhattacharjee, Mrinal K. ;
Bommareddy, Praveen K. ;
DePass, Anthony L. .
ANTIBIOTICS-BASEL, 2021, 10 (08)
[4]   Renal fibrosis: novel insights into mechanisms and therapeutic targets [J].
Boor, Peter ;
Ostendorf, Tammo ;
Floege, Juergen .
NATURE REVIEWS NEPHROLOGY, 2010, 6 (11) :643-656
[5]  
BORDER WA, 1994, NEW ENGL J MED, V331, P1286
[6]   Cellular Origin and Functional Relevance of Collagen I Production in the Kidney [J].
Buchtler, Simone ;
Grill, Alexandra ;
Hofmarksrichter, Stefanie ;
Stoeckert, Petra ;
Schiechl-Brachner, Gabriela ;
Gomez, Manuel Rodriguez ;
Neumayer, Sophia ;
Schmidbauer, Kathrin ;
Talke, Yvonne ;
Klinkhammer, Barbara M. ;
Boor, Peter ;
Medvinsky, Alexander ;
Renner, Kerstin ;
Castrop, Hayo ;
Mack, Matthias .
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2018, 29 (07) :1859-1873
[7]   Identification of serum metabolites associating with chronic kidney disease progression and anti-fibrotic effect of 5-methoxytryptophan [J].
Chen, Dan-Qian ;
Cao, Gang ;
Chen, Hua ;
Argyopoulos, Christos P. ;
Yu, Hui ;
Su, Wei ;
Chen, Lin ;
Samuels, David C. ;
Zhuang, Shougang ;
Bayliss, George P. ;
Zhao, Shilin ;
Yu, Xiao-Yong ;
Vaziri, Nosratola D. ;
Wang, Ming ;
Liu, Dan ;
Mao, Jia-Rong ;
Ma, Shi-Xing ;
Zhao, Jin ;
Zhang, Yuan ;
Shan, You-Quan ;
Kang, Huining ;
Ye, Fei ;
Cheng, Xiao-Hong ;
Li, Xiang-Ri ;
Zhang, Li ;
Meng, Mei-Xia ;
Guo, Yan ;
Zhao, Ying-Yong .
NATURE COMMUNICATIONS, 2019, 10
[8]   Telbivudine attenuates UUO-induced renal fibrosis via TGF-β/Smad and NF-κB signaling [J].
Chen, Jie ;
Li, Detian .
INTERNATIONAL IMMUNOPHARMACOLOGY, 2018, 55 :1-8
[9]   Extracellular matrix signaling in morphogenesis and repair [J].
Clause, Kelly C. ;
Barker, Thomas H. .
CURRENT OPINION IN BIOTECHNOLOGY, 2013, 24 (05) :830-833
[10]   Chrysophanol ameliorates renal interstitial fibrosis by inhibiting the TGF-β/Smad signaling pathway [J].
Dou, Fang ;
Ding, Yi ;
Wang, Cheng ;
Duan, Jialin ;
Wang, Wenjun ;
Xu, Hang ;
Zhao, Xian ;
Wang, Jingwen ;
Wen, Aidong .
BIOCHEMICAL PHARMACOLOGY, 2020, 180