Original articleErhuang Formula ameliorates renal damage in adenine–induced chronic renal failure rats via inhibiting inflammatory and fibrotic responses
Introduction
Chronic renal failure (CRF) is a common consequence in a variety of chronic kidney diseases (CKD), which has become an important public health problem in China [1]. The progression of CRF is characterized by the development of glomerular and tubular lesions in which multiple factors can be involved [2]. Although much is known about the progression of CRF, there are not any effective treatments to hold back or treat CRF. Therefore, the development of successful therapeutic strategies remains a clinical challenge [3].
As we know, Traditional Chinese medicines (TCMs) had a long history dating back several thousands of years for clinical application and the discovery of new drugs [4], [5], [6]. Many TCMs possessed long time clinical application as well as beneficial and reliable therapeutic efficacy and they are attracting increased global attention for the treatment of CRF [7], [8], [9], [10], [11], [12]. Chinese herbal formula (CHF), a herbal mixture prescription, has been used for the treatment of various of diseases and syndromes [13]. Many previous studies focused on the renal protective effects of CHF [14], [15], [16]. Erhuang Formula (EHF) is a classical formula for treating kidney injury, which is composed of Astragali radix, Rhei radix etrhizoma, Trigonellae semen, Achyranthis bidentatae radix, Vaccariae semen, Smilacis glabrae rhizoma, Curcumae rhizome (Table 1). EHF has an obvious improvement for CRF patients, and it has been reported that EHF exerted significant protective effects for the treatment of renal fibrosis in CRF rats [17]. However, the mechanisms of its pharmacological effects are still unclear.
Accumulating evidence indicates that inflammatory and fibrotic responses play a significant role in CRF progression and development [18]. Activated nuclear factor-kappaB signaling pathway and pro-inflammatory cytokine tumor necrosis factor (TNF-α) and pro-fibrogenic cytokine transforming growth factor beta 1 (TGF-β1) contribute to the damage of renal failure [19], [20]. Inflammatory stimuli have been found to active resident fibroblasts, and inhibition of inflammation attenuated profibrogenic gene expression and tubulointerstitial fibrosis in kidney diseases. Furthermore, an overview of kidney diseases shows that complementary but different mechanisms are responsible for fibrosis [21]. The adenine-induced CRF model was first reported in rats about thirty years ago [22]. This model was widely used for inflammation and metabolism dysregulation–associated action mechanism of CRF [23], [24] and efficacy evaluation and therapeutic mechanism of TCMs such as Poria cocos [25], [26], [27], Rheum officinale [28], [29], [30], [31] and Polyporus umbellatus [32], [33], [34]. This kind of CRF model can provide valuable information of pathological mechanisms for various complications in a persistent uremic state, and long-term feeding adenine to rats could cause metabolic abnormalities similar to the CKD symptoms in humans [35]. Therefore, in the present study, the adenine-induced CRF model was used to evaluate the protective effects of EHF and explore its pharmacological mechanisms.
Section snippets
Materials
Preparation of Erhuang Formula: EHF was prepared and purchased from Shanghai Chinese Medicine Pharmaceutical Technology Ltd. (Shanghai, China), and the preparation method was as follows. The air-dried herbs identified by authority were powdered and subjected to reflux extraction with 10 times water for 1 h. The aqueous extracts were filtered and collected. The extraction was repeated twice with the method introduced above, and then all the extracts were evaporated to dryness under reduced
Identification of ten compounds in EHF
The aqueous extract of mixed ten Chinese medicinal materials was measured by HPLC/ESI–MS in negative and positive-ion mode (Fig. 1A-L). Ten compounds 1 − 10, with the retention time at 3.59 min, 4.73 min, 4.94 min, 5.01 min, 5.42 min, 5.95 min, 6.92 min, 8.89 min, 10.18 min, and 10.25 min, were identified as liquiritigenin (1), farnesene (2), vaccarin (3), pachymic acid (4), cycloastragenol (5), astilbin (6), 3,5,6,7,8,3′,4′-heptemthoxyflavone (7), physcion (8), emodin (9), and curzerene (10), on the basis
Discussion
The effective therapy of CRF remains a major unmet clinical medical need. Adenine produces metabolic abnormalities resembling chronic renal insufficiency in humans [22], [36]. The present study showed the protective effect of EHF on CRF rats induced by adenine. We examined renal function including Scr and BUN and histology. Significantly increased Scr and BUN concentrations are observed in our study, which are consistent with the previous publications [37], [38], [39]. Furthermore, histological
Conflict of interests
The authors have declared that there is no conflict of interests.
Acknowledgments
This work was supported by National Natural Science Foundation of China (grant number 81503332), Shanghai Municipal Health and Family Planning Commission (grant number ZY3-JSFC-2-2010, 20154Y0063), Outstanding Leaders Training Program of Pudong Health Bureau of Shanghai (grant number PWR12015-05), Excellent Youth Medical Talents Training Program of Pudong Health Bureau of Shanghai (grant number PWRq2015-11), and the Open Research Fund of State Key Laboratory Breeding Base of Systematic
References (65)
Prevalence of chronic kidney disease in China: a cross-sectional survey
Lancet
(2012)New model for adenine-induced chronic renal failure in mice, and the effect of gum acacia treatment thereon: comparison with rats
J. Pharmacol. Toxicol. Methods
(2013)Ureic clearance granule: alleviates renal dysfunction and tubulointerstitial fibrosis by promoting extracellular matrix degradation in renal failure rats, compared with enalapril
J. Ethnopharmacol.
(2014)Metabolomics highlights pharmacological bioactivity and biochemical mechanism of traditional Chinese medicine
Chem. Biol. Interact.
(2017)Therapeutic use of traditional Chinese herbal medications for chronic kidney diseases
Kidney Int.
(2013)Metabolomic application in toxicity evaluation and toxicological biomarker identification of natural product
Chem. Biol. Interact.
(2016)Traditional uses, phytochemistry, pharmacology, pharmacokinetics and quality control of Polyporus umbellatus (Pers.) Fries: a review
J. Ethnopharmacol.
(2013)Urinary metabonomics study on the protective effects of ergosta-4,6,8(14),22-tetraen-3-one on chronic renal failure in rats using UPLC Q-TOF/MS and a novel MSE data collection technique
Process Biochem.
(2012)- et al.
Traditional uses, phytochemistry, pharmacology, toxicology and quality control of Alisma orientale (Sam.) Juzep: a review
J. Ethnopharmacol.
(2014) Recent advances in traditional Chinese medicine for kidney disease
Am. J. Kidney Dis.
(2015)
UPLC-Q-TOF/HSMS/MS(E)-based metabonomics for adenine-induced changes in metabolic profiles of rat faeces and intervention effects of ergosta-4,6,8(14),22-tetraen-3-one
Chem. Biol. Interact.
Traditional uses, fermentation, phytochemistry and pharmacology of Phellinus linteus: a review
Fitoterapia
Huangqi decoction alleviates dimethylnitrosamine-induced liver fibrosis: an analysis of bile acids metabolic mechanism
J. Ethnopharmacol.
Dahuang Fuzi Decoction ameliorates tubular epithelial apoptosis and renal damage via inhibiting TGF-beta1-JNK signaling pathway activation in vivo
J. Ethnopharmacol.
You-gui Pill ameliorates renal tubulointerstitial fibrosis via inhibition of TGF-beta/Smad signaling pathway
J. Ethnopharmacol.
Renal metabolic profiling of early renal injury and renoprotective effects of Poria cocos epidermis using UPLC Q-TOF/HSMS/MSE
J. Pharm. Biomed. Anal.
Urinary metabonomic study of the surface layer of Poria cocos as an effective treatment for chronic renal injury in rats
J. Ethnopharmacol.
Rhein reverses Klotho repression via promoter demethylation and protects against kidney and bone injuries in mice with chronic kidney disease
Kidney Int.
Effect of ergosta-4,6,8(14),22-tetraen-3-one (ergone) on adenine-induced chronic renal failure rat: a serum metabonomic study based on ultra performance liquid chromatography/high-sensitivity mass spectrometry coupled with MassLynx i-FIT algorithm
Clin. Chim. Acta
Effect and mechanism of fucoidan derivatives from Laminaria japonica in experimental adenine-induced chronic kidney disease
J. Ethnopharmacol.
Urinary metabonomics study on biochemical changes in an experimental model of chronic renal failure by adenine based on UPLC Q-TOF/MS
Clin. Chim. Acta
A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis
Mol. Cell
Transcription factor-kappa b (NF-kappa B) and renal disease
Kidney Int.
Gene and protein expressions and metabolomics exhibit activated redox signaling and wnt/β-catenin pathway are associated with metabolite dysfunction in patients with chronic kidney disease
Redox Biol.
Metabolomics insights into activated redox signaling and lipid metabolism dysfunction in chronic kidney disease progression
Redox Biol.
Transforming growth factor-beta regulates tubular epithelial-myofibroblast transdifferentiation in vitro
Kidney Int.
Role of RAS/Wnt/beta-catenin axis activation in the pathogenesis of podocyte injury and tubulo-interstitial nephropathy
Chem. Biol. Interact.
The interdependence of EGF-R and SGK-1 in fibronectin expression in primary kidney cortical fibroblast cells
Int. J. Biochem. Cell Biol.
Protective effects of bu-Shen-Huo-Xue formula against 5/6 nephrectomy-Induced chronic renal failure in rats
Evid. Based Complement. Alternat. Med.
Protective effect of the Erhuang compound remedy on the rats with kidney subtotal excision
Anhui Med. Pharm. J.
Metabolomics analysis reveals the association between lipid abnormalities and oxidative stress, inflammation, fibrosis, and Nrf2 dysfunction in aristolochic acid-induced nephropathy
Sci. Rep.
Docosahexaenoic acid ameliorates murine ischemic acute renal failure and prevents increases in mRNA abundance for both TNF-alpha and inducible nitric oxide synthase
J. Am. Soc. Nephrol.
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