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.
Highlights
Nephrolithiasis remains one of the most common and highly recurrent urological diseases worldwide [1]
We aim to investigate whether blockage of L-type Ca2+ channels or Wnt11 could significantly attenuate the epithelial to mesenchymal transition (EMT) process in an idiopathic hypercalciuria (IH) rat model and further study the effects of calcium and transforming growth factor-β1 (TGF-β1) on cellular differentiation in
We found that TGF-β1 expression in renal artery and vein were increased in genetic hypercalciuric stone-forming (GHS) rats (n = 15, Figure 1A,C) (p < 0.01)
Summary
Nephrolithiasis remains one of the most common and highly recurrent urological diseases worldwide [1]. The complicated mechanism of nephrolithiasis has not been fully elucidated to date yet. The biochemical basis for stone formation is supersaturation of urine with relation to the stone minerals, involving increased supersaturation of calcium and oxalate [2]. Recent data reported that as many as 30%–50% of male stone formers investigated in stone clinics have hypercalciuria, which in most cases is idiopathic [3]. Idiopathic hypercalciuria (IH) is the finality of the interaction between genetic background and environment. IH may involve the dysregulation of multiple calcium transport systems, including increased intestinal absorption of calcium, primary renal leak of calcium (decreased renal calcium reabsorption) and increased bone demineralization [4,5]
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