Abstract
Melamine, which induces proximal tubular (PT) cell damage has a greater nephrotoxic effect when combined with cyanuric and uric acids; however, it is unknown whether such effect can stimulate calcium phosphate (CaP)/calcium oxalate (CaOx) stone formation. Here, we show that melamine acts as an inducer of CaP, CaOx and CaP + CaOx (mixed) crystal formations in a time and concentration-dependent manner by stabilizing those crystals and further co-aggregating with melamine. To explore the physiological relevance of such melamine-augmented calcium crystal formation, we used 2-dimensional (2D) and 3D microfluidic (MF) device, embedded with PT cells, which also resembled the effect of melamine-stimulated CaP, CaOx and mixed crystal formation. Significantly, addition of preformed CaP and/or CaOx crystal in the presence of melamine, further potentiated those crystal formations in 3D MFs, which helped the growth and aggregation of mixed crystals. Our data show that the mechanism of such predisposition of stone formation could be largely due to co-crystallization between melamine and CaP/CaOx and pronounced effect on induction of stone-forming pathway activation in 3D MF. Taken together, melamine-induced CaP and/or CaOx crystal formation ex-vivo will help us in understanding the larger role of melamine as an environmental toxicant in producing the pathology in similar cellular microenvironments.
Highlights
The prevalence and frequency of calcium stones, which account for more than 70% of all nephrolithiasis, increased in the last decade[1,2]
Our results show, for the first time, that preformed calcium phosphate (CaP) and melamine promote calcium crystal formations, necrosis and apoptosis under physiological 3D MF constructed with proximal tubular (PT) cells, suggesting that melamine can create a pathologic condition of mixed calcium crystal formations by modulating the PT cellular microenvironment
We used a non-cellular environment to avoid the complexity of cellular system and observed that melamine can induce CaP, calcium oxalate (CaOx) and mixed crystal formation almost instantaneously in a concentration dependent manner
Summary
The prevalence and frequency of calcium stones, which account for more than 70% of all nephrolithiasis, increased in the last decade[1,2]. Among the possible factors for this increase, a synthetic compound, melamine, which has a broad spectrum use in plastics, dishware, kitchen utensils and adhesives[14], has been shown to contribute to acute kidney injury and kidney stone diseases[15]. Several studies along these lines identified the downstream intracellular pathways of melamine-induced renal cytotoxicity resulting in increased inflammation and oxidative stress[16] and excessive intracellular reactive oxygen species (ROS) production[17], leading to apoptosis. We show here the contribution of melamine in CaP, CaOx and mixed stone formation, including a cellular microenvironment, and went above and beyond by utilizing a vivo-like 3D MF cellular environment to explore such effects of melamine exposure, ensuring the possibility and its pathophysiological relevance in CaP/CaOx stone formation
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