The Wnt11 Signaling Pathway in Potential Cellular EMT and Osteochondral Differentiation Progression in Nephrolithiasis Formation

International Journal of Molecular Sciences

Deng He³  Yuchao Lu³  Henglong Hu³  Jiaqiao Zhang³  Baolong Qin³  Yufeng Wang³  Shuai Xing¹  Qilin Xi²  Shaogang Wang³ 

[1] Department of Gastroenterology, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; E-Mail:;Department of Urology, the First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China; E-Mail:;Department of Urology, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; E-Mails:

关键词: TGF-β1;    calcium channel;    Wnt11;    nephrolithiasis;   

DOI  :  10.3390/ijms160716313

来源: mdpi

【 摘 要 】

The molecular events leading to nephrolithiasis are extremely complex. Previous studies demonstrated that calcium and transforming growth factor-β1 (TGF-β1) may participate in the pathogenesis of stone formation, but the explicit mechanism has not been defined. Using a self-created genetic hypercalciuric stone-forming (GHS) rat model, we observed that the increased level of serous/uric TGF-β1 and elevated intracellular calcium in primary renal tubular epithelial cells (PRECs) was associated with nephrolithiasis progression in vivo. In the setting of high calcium plus high TGF-β1 in vitro, PRECs showed great potential epithelial to mesenchymal transition (EMT) progression and osteochondral differentiation properties, representing the multifarious increased mesenchymal and osteochondral phenotypes (Zeb1, Snail1, Col2A1, OPN, Sox9, Runx2) and decreased epithelial phenotypes (E-cadherin, CK19) bythe detection of mRNAs and corresponding proteins. Moreover, TGF-β-dependent Wnt11 knockdown and L-type Ca²⁺ channel blocker could greatly reverse EMT progression and osteochondral differentiation in PRECs. TGF-β1 alone could effectively promote EMT, but it had no effect on osteochondral differentiation in NRK cells (Rat kidney epithelial cell line). Stimulation with Ca²⁺ alone did not accelerate differentiation of NRK. Co-incubation of extracellular Ca²⁺ and TGF-β1 synergistically promotes EMT and osteochondral differentiation in NRK control cells. Our data supplied a novel view that the pathogenesis of calcium stone development may be associated with synergic effects of TGF-β1 and Ca²⁺, which promote EMT and osteochondral differentiation via Wnt11 and the L-type calcium channel.

【 授权许可】

CC BY   
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