Lei La1, Lili Wang2, Fei Qin3, Jian Jiang4, Songqi He5, Chunxia Wang6, Yuhao Li7. 1. Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. Electronic address: lalei@smu.edu.cn. 2. Department of Pharmacy, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China. Electronic address: 1039875614@qq.com. 3. Guangzhou Baiyunshan Pharmaceutical Holdings CO. Ltd, BAIYUNSHAN Pharmaceutical General Factory, Guangzhou 510515, China. Electronic address: 102536@byszc.com. 4. Endocrinology and Metabolism Group, Sydney Institute of Health Sciences/Sydney Institute of Traditional Chinese Medicine, NSW 2000, Australia. Electronic address: jianjiangau@gmail.com. 5. College of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China. Electronic address: hesongqi@smu.edu.cn. 6. Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Guangdong Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: wangcx@smu.edu.cn. 7. Endocrinology and Metabolism Group, Sydney Institute of Health Sciences/Sydney Institute of Traditional Chinese Medicine, NSW 2000, Australia. Electronic address: yuhao@sitcm.edu.au.
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE: Zhen-wu-tang (ZWT), composed of Radix Aconiti lateralis, Rhizoma Atractylodis macrocephalae, Poria, Radix Paeoniae alba and ginger, is a classic Chinese herbal formula for the treatment of chronic kidney diseases that may cause chronic renal failure (CRF). AIM OF THE STUDY: To better understand its clinical use, this study investigated the effects and underlying mechanisms of action of ZWT on CRF. MATERIALS AND METHODS: CRF was induced by adenine. ZWT was given via an oral gavage method. The serum biochemical parameters were measured enzymatically or by ELISA. The kidneys were examined pathohistologically. The gene expression was analyzed by real time PCR and Western blot. RESULTS: Similar to the positive control losartan, ZWT extract inhibited adenine-induced increase in serum concentrations of creatinine, BUN and advanced oxidation protein products in rats. These effects were accompanied by attenuation of proteinuria and renal pathological changes and suppression of renal mRNA and protein overexpression of Collagen IV and fibronectin, two of the key components of fibrosis. Mechanistically, renal mRNA and protein expression of Wnt4, a Wnt signaling ligand, was increased in the adenine-treated group, compared to the vehicle-treated control. Consistently, Wnt4 downstream genes beta-catenin and Axin were also overexpressed. Treatment with ZWT extract and losartan suppressed adenine-stimulated overexpression of these mRNAs and proteins. CONCLUSIONS: The present results demonstrate that ZWT extract ameliorates adenine-induced CRF in rats by regulation of the canonical Wnt4/beta-catenin signaling in the kidneys. Our findings provide new insight into the underlying renoprotective mechanisms of the ancient formula.
ETHNOPHARMACOLOGICAL RELEVANCE: Zhen-wu-tang (ZWT), composed of Radix Aconiti lateralis, Rhizoma Atractylodis macrocephalae, Poria, Radix Paeoniae alba and ginger, is a classic Chinese herbal formula for the treatment of chronic kidney diseases that may cause chronic renal failure (CRF). AIM OF THE STUDY: To better understand its clinical use, this study investigated the effects and underlying mechanisms of action of ZWT on CRF. MATERIALS AND METHODS: CRF was induced by adenine. ZWT was given via an oral gavage method. The serum biochemical parameters were measured enzymatically or by ELISA. The kidneys were examined pathohistologically. The gene expression was analyzed by real time PCR and Western blot. RESULTS: Similar to the positive control losartan, ZWT extract inhibited adenine-induced increase in serum concentrations of creatinine, BUN and advanced oxidation protein products in rats. These effects were accompanied by attenuation of proteinuria and renal pathological changes and suppression of renal mRNA and protein overexpression of Collagen IV and fibronectin, two of the key components of fibrosis. Mechanistically, renal mRNA and protein expression of Wnt4, a Wnt signaling ligand, was increased in the adenine-treated group, compared to the vehicle-treated control. Consistently, Wnt4 downstream genes beta-catenin and Axin were also overexpressed. Treatment with ZWT extract and losartan suppressed adenine-stimulated overexpression of these mRNAs and proteins. CONCLUSIONS: The present results demonstrate that ZWT extract ameliorates adenine-induced CRF in rats by regulation of the canonical Wnt4/beta-catenin signaling in the kidneys. Our findings provide new insight into the underlying renoprotective mechanisms of the ancient formula.