Blocking TGF- and -Catenin Epithelial Crosstalk Exacerbates CKD. Nlandu-Khodo Stellor,Neelisetty Surekha,Phillips Melanie,Manolopoulou Marika,Bhave Gautam,May Lauren,Clark Peter E,Yang Haichun,Fogo Agnes B,Harris Raymond C,Taketo M Mark,Lee Ethan,Gewin Leslie S Journal of the American Society of Nephrology : JASN The TGF- and Wnt/-catenin pathways have important roles in modulating CKD, but how these growth factors affect the epithelial response to CKD is not well studied. TGF- has strong profibrotic effects, but this pleiotropic factor has many different cellular effects depending on the target cell type. To investigate how TGF- signaling in the proximal tubule, a key target and mediator of CKD, alters the response to CKD, we injured mice lacking the TGF- type 2 receptor specifically in this epithelial segment. Compared with littermate controls, mice lacking the proximal tubular TGF- receptor had significantly increased tubular injury and tubulointerstitial fibrosis in two different models of CKD. RNA sequencing indicated that deleting the TGF- receptor in proximal tubule cells modulated many growth factor pathways, but Wnt/-catenin signaling was the pathway most affected. We validated that deleting the proximal tubular TGF- receptor impaired -catenin activity and Genetically restoring -catenin activity in proximal tubules lacking the TGF- receptor dramatically improved the tubular response to CKD in mice. Deleting the TGF- receptor alters many growth factors, and therefore, this ameliorated response may be a direct effect of -catenin activity or an indirect effect of -catenin interacting with other growth factors. In conclusion, blocking TGF- and -catenin crosstalk in proximal tubules exacerbates tubular injury in two models of CKD. 10.1681/ASN.2016121351

FoxM1 promotes Wnt/β-catenin pathway activation and renal fibrosis via transcriptionally regulating multi-Wnts expressions. Xie Hongyan,Miao Naijun,Xu Dan,Zhou Zhuanli,Ni Jiayun,Yin Fan,Wang Yanzhe,Cheng Qian,Chen Panpan,Li Jingyao,Zheng Peiqing,Zhou Li,Liu Jun,Zhang Wei,Wang Xiaoxia,Lu Limin Journal of cellular and molecular medicine The activation of Wnt/β-catenin pathway plays a pivotal role in promoting renal fibrosis. The activation of Wnt/β-catenin pathway relies on the binding of Wnts to Frizzled receptors on cell membrane. However, the factor regulating Wnts production remains unclear. Here, we demonstrated that transcriptional factor FoxM1 was significantly increased in obstructed kidneys and patients' kidneys with fibrosis. The up-regulation of FoxM1 mainly distributed in tubular epithelial cells. Pharmacological inhibition of FoxM1 down-regulated multi-Wnts elevation in UUO mice and attenuated renal fibrosis. In cultured renal tubular epithelial cells, overexpression of FoxM1 promoted 8 Wnts expression, while knock-down on FoxM1-suppressed multi-Wnts including Wnt1, Wnt2b and Wnt3 expression induced by Ang II. Chromatin immunoprecipitation PCR confirmed that FoxM1 bound to Wnt1, Wnt2b, Wnt3 promoters and luciferase assay further identified that the transcriptions of Wnt1, Wnt2b and Wnt3 were regulated by FoxM1. Thus, our findings show that multi-Wnt family members were regulated by transcriptional factor FoxM1. FoxM1 might be a key switch for activating β-catenin pathway and renal fibrosis. Therefore, FoxM1 might be a potential therapeutic target in manipulating renal fibrosis. 10.1111/jcmm.15948

Defective CFTR leads to aberrant β-catenin activation and kidney fibrosis. Zhang Jie Ting,Wang Yan,Chen Jun Jiang,Zhang Xiao Hu,Dong Jian Da,Tsang Lai Ling,Huang Xiao Ru,Cai Zhiming,Lan Hui Yao,Jiang Xiao Hua,Chan Hsiao Chang Scientific reports Cystic fibrosis transmembrane conductance regulator (CFTR), known as a cAMP-activated Cl channel, is widely expressed at the apical membrane of epithelial cells in a wide variety of tissues. Of note, despite the abundant expression of CFTR in mammalian kidney, the role of CFTR in kidney disease development is unclear. Here, we report that CFTR expression is downregulated in the UUO (unilateral ureteral obstruction)-induced kidney fibrosis mouse model and human fibrotic kidneys. Dysfunction or downregulation of CFTR in renal epithelial cells leads to alteration of genes involved in Epithelial-Mesenchymal Transition (EMT) and kidney fibrosis. In addition, dysregulation of CFTR activates canonical Wnt/β-catenin signaling pathways, whereas the β-catenin inhibitor reverses the effects of CFTR downregulation on EMT marker. More interestingly, CFTR interacts with Dishevelled 2 (Dvl2), a key component of Wnt signaling, thereby suppressing the activation of β-catenin. Compared to wild type, deltaF508 mice with UUO treatment exhibit significantly higher β-catenin activity with aggregated kidney fibrogenesis, which is reduced by forced overexpression of CFTR. Taken together, our study reveals a novel mechanism by which CFTR regulates Wnt/β-catenin signaling pertinent to progression of kidney fibrosis and indicates a potential treatment target. 10.1038/s41598-017-05435-5

Protective role of kallistatin in renal fibrosis via modulation of Wnt/β-catenin signaling. Clinical science (London, England : 1979) Kallistatin is a multiple functional serine protease inhibitor that protects against vascular injury, organ damage and tumor progression. Kallistatin treatment reduces inflammation and fibrosis in the progression of chronic kidney disease (CKD), but the molecular mechanisms underlying this protective process and whether kallistatin plays an endogenous role are incompletely understood. In the present study, we observed that renal kallistatin levels were significantly lower in patients with CKD. It was also positively correlated with estimated glomerular filtration rate (eGFR) and negatively correlated with serum creatinine level. Unilateral ureteral obstruction (UUO) in animals also led to down-regulation of kallistatin protein in the kidney, and depletion of endogenous kallistatin by antibody injection resulted in aggravated renal fibrosis, which was accompanied by enhanced Wnt/β-catenin activation. Conversely, overexpression of kallistatin attenuated renal inflammation, interstitial fibroblast activation and tubular injury in UUO mice. The protective effect of kallistatin was due to the suppression of TGF-β and β-catenin signaling pathways and subsequent inhibition of epithelial-to-mesenchymal transition (EMT) in cultured tubular cells. In addition, kallistatin could inhibit TGF-β-mediated fibroblast activation via modulation of Wnt4/β-catenin signaling pathway. Therefore, endogenous kallistatin protects against renal fibrosis by modulating Wnt/β-catenin-mediated EMT and fibroblast activation. Down-regulation of kallistatin in the progression of renal fibrosis underlies its potential as a valuable clinical biomarker and therapeutic target in CKD. 10.1042/CS20201161

Acylglycerol kinase promotes the stemness of nasopharyngeal carcinoma cells by promoting β-catenin translocation to the nucleus through activating PI3K/Akt pathway. Zhao Qi,Sun Peng,Qin Songbing,Liu Jisheng Environmental toxicology Recent evidences show that acylglycerol kinase (AGK) expression is related to the occurrence and development of various human cancers. However, its roles in nasopharyngeal carcinoma (NPC) progression are still unclear. This work aims to explore the roles of AGK in NPC cell stemness. It was shown that AGK expression was higher in NPC tissues compared to the adjacent tissues. Online dataset analysis revealed that AGK expression was negatively correlated with the overall survival of NPC patients. Gain and loss of functional experiments demonstrated that AGK positively regulated the stemness of NPC cells, as evident by the change of the tumor sphere-formation ability, ALDH1 activity and expression of stemness critical regulators. KEGG analysis were performed to determine the potential pathways of AGK involved in NPC cell stemness and showed that the PI3K/Akt pathway exhibited the most correlation with AGK expression. Further mechanistic studies confirmed that AGK promoted the stemness of NPC cells through activating the PI3K/Akt pathway, and thus enhancing β-catenin accumulation in nucleus. This study demonstrates a novel AGK/PI3K/Akt/β-catenin axis involving in NPC cell stemness. 10.1002/tox.22994