However, recent data also provide evidence for a function of calponin-3 beyond neurogenesis

ed after 48h. Furthermore, the fact that cytotoxity was only seen at higher concentrations is in accordance with in vivo observations showing that renal damage declines when the dose is reduced and with data from clinical studies demonstrating renal toxicity to be absent in postmenopausal women that Vorapaxar web receive zoledronic acid at relatively low annual dose. These observations can be explained by the fact that protein prenylation must be reduced to below a critical level before cytotoxicity eventually occurs. In conclusion, this manuscript presents evidence that zoledronic acid is internalized by renal tubular cells via the process of fluid phase endocytosis. The intracellular presence of zoledronic acid may induce tubular cytotoxicity provided its intracellular concentrations reach a 16 / 19 Renal Handling of Zoledronic Acid Fig 11. Administered concentration-dependence of zoledronic acid fluxes. and intracellular zoledronic acid concentration. Zoledronic acid transport and intracellular accumulation was measured in confluent monolayers of primary human tubular cells using the steady state set-up. This figure represents the results of one representative experiment on cells originating from one kidney. doi:10.1371/journal.pone.0121861.g011 high enough level. Our findings may contribute to a better understanding of the observed PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19763871 renal damage in particular patient populations receiving zoledronic acid at high doses. Acknowledgments This work would not have been possible without the generous cooperation of Dr Pozdzik and Dr Rorive. We also thank Simonne Dauwe and Dirk De Weerdt for their tremendous assistance in cell culturing and graphics, respectively. Sofie Thijs is thanked for her excellent support with confocal microscopy Dr. Ursula Schramm and Dr. Jonathan Green we want to thank for helpful discussions. ~~ ~~ LPA is a potent signaling lipid molecule that is involved in numerous phenomena, such as cell migration, preventing cellular apoptosis, angiogenesis, and others. LPA modulates its biological functions through the activation of at least six G-protein-coupled receptors . Liver regeneration is an important phenomenon after liver injury, and PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19761601 the reproducibility of a partial hepatectomy model has made it the preferred approach for studies on liver regeneration. Many studies have demonstrated that exogenous factors, such as pharmaceutical agents like acetaminophen, chemicals like CCl4, and endogenous factors, such as angiotensinogen, IL-6, and interferon gamma receptors, are critically involved in liver regeneration. Ikeda et al. first demonstrated that LPA might affect the proliferation of hepatocytes and stellate cells in those liver diseases that disrupted platelet activation. Recently, by using a partial hepatectomy mouse model, Simo et al. found that liver regeneration after partial hepatectomy was associated with significant changes in circulating LPA levels and that hepatic mRNA levels of LPAR1, LPAR3, and LPAR6 were expressed in a time- and cell-dependent manner. Additionally, their immunohistochemical staining results revealed that LPAR1 protein was expressed in non-parenchyma cells, and that LPAR3 and LPAR6 proteins were widely distributed in regenerating liver tissue. The study by Simo et al. clearly demonstrated the phenomena of increased LPA levels and expression levels of LPAR’s during liver regeneration. LPA receptors were originally defined as an endothelium differentiation gene subfamily of G-protein-coupled receptors. Live