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Int. J. Mol. Sci. 2015, 16(7), 16313-16329; doi:10.3390/ijms160716313

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

1
Department of Urology, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
2
Department of Gastroenterology, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
3
Department of Urology, the First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China
*
Author to whom correspondence should be addressed.
Academic Editor: Regina M. Day
Received: 30 April 2015 / Revised: 22 June 2015 / Accepted: 7 July 2015 / Published: 17 July 2015
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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Abstract

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. View Full-Text
Keywords: TGF-β1; calcium channel; Wnt11; nephrolithiasis TGF-β1; calcium channel; Wnt11; nephrolithiasis
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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He, D.; Lu, Y.; Hu, H.; Zhang, J.; Qin, B.; Wang, Y.; Xing, S.; Xi, Q.; Wang, S. The Wnt11 Signaling Pathway in Potential Cellular EMT and Osteochondral Differentiation Progression in Nephrolithiasis Formation. Int. J. Mol. Sci. 2015, 16, 16313-16329.

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