Baicalein attenuates renal fibrosis by inhibiting inflammation via down-regulating NF-κB and MAPK signal pathwaysby Wei Wang, Pang-hu Zhou, Chang-geng Xu, Xiang-jun Zhou, Wei Hu, Jie Zhang

Journal of Molecular Histology


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Baicalein attenuates renal fibrosis by inhibiting inflammation via down-regulating NF-jB and MAPK signal pathways

Wei Wang1 • Pang-hu Zhou2 • Chang-geng Xu1 •

Xiang-jun Zhou1 • Wei Hu1 • Jie Zhang1,3

Received: 14 March 2015 / Accepted: 11 May 2015  Springer Science+Business Media Dordrecht 2015

Abstract Baicalein is a natural flavonoid that possesses notable anti-inflammatory effects. In this study, we detected whether baicalein protects against inflammatory response in unilateral ureteral obstruction mice model to ameliorate tubulointerstitial fibrosis. Baicalein treatment significantly attenuated tubulointerstitial fibrosis by markedly reducing fibronectin and collagen-I. The downregulation of alpha-smooth muscle actin and upregulation of E-cadherin indicated that the epithelial–mesenchymal transition process was suppressed. Furthermore, baicalein administration blocked the infiltration of macrophages and lymphocytes, as evidenced by the significantly reduced

CD68 and CD3 positive cells. Meanwhile, the mRNA expression of the pro-inflammatory cytokines tumor necrosis factor-a, interleukin-1b, and monocyte chemotactic protein in baicalein-treated groups was markedly reduced compared with the vehicle-treated group. More importantly, unilateral ureteral obstruction induced the activation of NFjB and mitogen-activated protein kinase signal pathways to switch on inflammatory response to aggravate kidney fibrosis, but these effects were mitigated by baicalein.

These data demonstrate that baicalein could inhibit inflammatory process via inactivation of NF-jB and

MAPK signal pathways to execute its anti-fibrotic actions in obstructive kidney disease.

Keywords Baicalein  CKDs  Inflammation 



Chronic kidney disease (CKD) is a global health issue and considered as an irreversible process that leads to poor prognosis. Renal fibrosis, especially renal interstitial fibrosis, is a final common outcome caused by progressive loss of renal function in varied CKDs, as well as a major force leads CKDs to end stage renal disease (Ni et al. 2013). Unilateral ureteral obstruction (UUO) is a common animal model widely used to mimic the pathological changes of chronic obstructive nephropathy. This model can reflect inflammatory responses and fibrosis in human

CKD. UUO is characterized by increased intraluminal pressure, interstitial inflammation, immediate macrophage and lymphocyte infiltration, evaluated cytokine levels, activation of myofibroblasts, and accumulation of interstitial extracellular matrix (ECM) (Eddy 2014). Previous studies demonstrated that inflammatory cells are recruited to the renal interstitium after UUO; these cells generate numerous cytokines and growth factors, which sustain and enhance inflammatory response (Crisman et al. 2001; Schreiner et al. 1988). Chronic interstitial inflammation, followed by functional renal parenchyma loss and interstitial fibrosis, mainly contributes to the deprivation of the renal function (Klahr and Morrissey 2002). Therefore, suppressing inflammatory response could attenuate renal fibrosis.

Wei Wang and Pang-hu Zhou have contributed equally to this article. & Jie Zhang 1 Department of Urology, Renmin Hospital of Wuhan

University, 99 Ziyang Road, Wuhan 430060, Hubei Province,

China 2 Department of Orthopedics, Renmin Hospital of Wuhan

University, 99 Ziyang Road, Wuhan 430060, Hubei Province,

China 3 Huangshi Central Hospital, Hubei Polytechnic University, 141 Tianjin Road, Huangshi 435000, Hubei Province, China 123

J Mol Hist

DOI 10.1007/s10735-015-9621-8

Baicalein (5,6,7-trihydroxyflavone) is a natural flavonoid extracted from the Chinese herb Scutellaria baicalensis (Hou et al. 2011). It has been widely used as a therapeutic agent for microbial infection in East Asian countries.

Moreover, baicalein possesses many biochemical and pharmacological benefits, including anti-tumor, anti-fibrogenic (Oh et al. 2012; Shimizu 2001), anti-inflammatory (Liu et al. 2014; Zhang et al. 2014), and cardiovascular protective effects. Baicalein has been increasingly used against renal (Wang et al. 2012), myocardial (Kong et al. 2011), pulmonary (Gao et al. 2013), and hepatic (Inoue and

Jackson 1999; Shimizu 2000; Sun et al. 2010) fibroses as a potential antioxidant. Intriguingly, several studies have also revealed the extensive anti-inflammatory effects of baicalein as a protective agent in various diseases. For example, Liu et al. (Liu et al. 2014) reported that baicalein can attenuate liver injury induced by polymicrobial sepsis by inhibiting inflammation. Furthermore, baicalein reduces airway inflammation in allergen and IL-1b-induced asthma model.

Baicalein also exhibits protective properties in kidney injury (Wu et al. 2014) and fibrosis (Wang et al. 2012). It promotes the recovery of renal function, alleviates kidney injury in ischemia–reperfusion (I/R) model, and ameliorates kidney fibrosis through downregulated TGF-b1 and Smad-2 in

UUO mice model. However, whether baicalein has an effect on inflammation in obstructed kidneys and the mechanisms involved in this response is not clearly elucidated. Given these data, we hypothesize that baicalein may have a potential to inhibit inflammation in UUO model to ameliorate renal fibrogenesis.

Materials and methods

Animal model

Forty male C57/BL6 mice (aged 6–8 weeks) were provided by Wuhan University Center for animal experiment (Wuhan, China). The Institutional Animal Care and Use

Committee of Wuhan University approved the animal work protocol, which was performed in accordance with the

Principles of Laboratory Animal Care (NIH publication

Vol. 25, No. 28, revised 1996). Left ureters of the mice were exposed and subsequently ligated to induce the UUO model as an established procedure (Eddy et al. 2012). Mice were then randomly divided into four groups (n = 10), namely, sham surgery, UUO plus vehicle (UUO ? V),

UUO plus 50 mg/kg/day baicalein (Nanjing Dilger Medical