Abstract
Crystal-cell interactions are a vital step toward kidney stone formation. However, its mechanisms remained unclear. Here, a protein-protein interaction (PPI) network analysis of a kidney stone revealed that the proteins were enriched in a posttranslational protein modification process in the endoplasmic reticulum (ER). The in vitro study showed that the markers of ER stress, including Bip and CHOP, were upregulated, PERK and ATF6 were activated, and XBP-1 mRNA was spliced. An ER stress-specific protein, caspase-12, was activated in the apoptotic cells induced by calcium oxalate monohydrate (COM) crystals. The treatment with tunicamycin, an ER stress inducer, promoted the crystal-cell adhesion assayed by atomic absorption, reduced cell viability assayed by MTT, and downregulated the expression of proteins involved in the crystal formations. The treatment with salubrinal, an ER stress inhibitor, reversed the above effects for both tunicamycin and COM crystals. The aforementioned main observations were supported by in vivo study. These data demonstrated that ER stress was an essentially biological process of crystal-cell interactions. Our findings suggest that blocking ER stress may become a potential approach to preventing a kidney stone.
Highlights
The incidence of kidney stone disease is about 2–5% of the population in Asia and 8–15% in Europe and North America [1]
A total of 839 candidate proteins were obtained after a name conversion and removing duplicates, and they were integrated into the InWeb database to construct a kidney stone protein-protein interaction (PPI) network
Salubrinal significantly increased the number of viable cells, compared to the group that was only exposed to calcium oxalate monohydrate (COM) crystals, in the 24th hour (Figure 4(d)). These results suggest that endoplasmic reticulum (ER) stress induced by both tunicamycin and calcium oxalate may promote crystal formation by increasing crystal-cell adhesion, affecting the expression of proteins involved in crystal formation such as OPN and matrix Gla protein (MGP) and reducing cell viability
Summary
The incidence of kidney stone disease is about 2–5% of the population in Asia and 8–15% in Europe and North America [1]. Kidney stone formation is a complex response of cells to the exposure to crystals; the precise mechanism causing crystal-cell interactions is still unclear Both a network analysis and a gene ontology (GO) analysis are rapidly becoming powerful tools in complex disease studies [3, 4]. Wright et al identified more than 1000 proteins by a urinary proteome analysis [13] These proteins may interact with each other to play a vital role in modulating crystal nucleation, growth, aggregation, and adhesion to renal epithelial cells. It provides us with a significant amount of unprocessed information for understanding crystal-cell interactions in the process of kidney stone formation
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