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Bi2Te3-based materials have been widely utilized for commercial bulk thermoelectric (TE) devices. For the manufacture of miniaturized TE devices, the large-scale deposition of high-performance Bi2Te3-based thin films is crucial. However, it has not yet been effectively resolved. Herein, the Bi0.5Sb1.5Te3 films with different thicknesses were grown on sapphire substrates by controlling the co-sputtering time. We reveal that the film thickness has a significant impact on the electrical transport properties. Due to the mutual influence of electrical conductivity and Seebeck coefficient, there exists an optimal thickness with the maximum power factor is as high as 2900 μW m−1 K−2. Therefore, systematic research on the thickness-dependent TE characteristics of Bi2Te3-based films and the deposition of high-performance films will provide important information for the large-scale development of high-performance micro-TE devices.

This review examines the role of fibroblast growth factor-23 (FGF-23) in mineral metabolism, innate immunity and adverse cardiovascular outcomes.FGF-23, produced by osteocytes in bone, activates FGFR/α-Klotho (α-Kl) complexes in the kidney. The resulting bone-kidney axis coordinates renal phosphate reabsorption with bone mineralization, and creates a counter-regulatory feedback loop to prevent vitamin D toxicity. FGF-23 acts to counter-regulate the effects of vitamin D on innate immunity and cardiovascular responses. FGF-23 is ectopically expressed along with α-Kl in activated macrophages, creating a proinflammatory paracrine signaling pathway that counters the antiinflammatory actions of vitamin D. FGF-23 also inhibits angiotensin-converting enzyme 2 expression and increases sodium reabsorption in the kidney, leading to hypertension and left ventricular hypertrophy. Finally, FGF-23 is purported to cause adverse cardiac and impair neutrophil responses through activation of FGFRs in the absence of α-Kl. Although secreted forms of α-Kl have FGF-23 independent effects, the possibility of α-Kl independent effects of FGF-23 is controversial and requires additional experimental validation.FGF-23 participates in a bone-kidney axis regulating mineral homeostasis, proinflammatory paracrine macrophage signaling pathways, and in a bone-cardio-renal axis regulating hemodynamics that counteract the effects of vitamin D.

Mechanisms underlying the association between fibroblastic growth factor 23 (FGF-23) and inflammation are uncertain. We found that FGF-23 was markedly up-regulated in LPS/INF-γ-induced proinflammatory M1 macrophages and Hyp mouse-derived peritoneal macrophages, but not in IL-4-induced M2 anti-inflammatory macrophages. NF-КB and JAK/STAT1 pathways mediated the increased transcription of FGF-23 in response to M1 polarization. FGF-23 stimulated TNF-α, but not IL-6, expression in M0 macrophages and suppressed Arginase-1 expression in M2 macrophages through FGFR-mediated mechanisms. 1,25(OH)2 D stimulated Arginase-1 expression and inhibited FGF-23 stimulation of TNF-α. FGF-23 has proinflammatory paracrine functions and counter-regulatory actions to 1,25(OH)2 D on innate immune responses.

Nephrotoxicity is common with the use of the chemotherapeutic agent cisplatin, but the cellular mechanisms that modulate the extent of injury are unknown. Cisplatin downregulates expression of the taurine transporter gene ( TauT ) in LLC-PK1 proximal tubular renal cells, and forced overexpression of TauT protects against cisplatin-induced apoptosis in vitro . Because the S3 segments of proximal tubules are the sites of both cisplatin-induced injury and adaptive regulation of the taurine transporter, we hypothesized that TauT functions as an anti-apoptotic gene and protects renal cells from cisplatin-induced nephrotoxicity in vivo . Here, we studied the regulation of TauT in cisplatin nephrotoxicity in a human embryonic kidney cell line and in LLC-PK1 cells, as well as in TauT transgenic mice. Cisplatin-induced activation of p53 repressed TauT and overexpression of TauT prevented the progression of cisplatin-induced apoptosis and renal dysfunction in TauT transgenic mice. Although cisplatin activated p53 and PUMA (a p53-responsive proapoptotic Bcl-2 family protein) in the kidneys of both wildtype and TauT transgenic mice, only wildtype animals demonstrated acute kidney injury. These data suggest that functional TauT plays a critical role in protecting against cisplatin-induced nephrotoxicity, possibly by attenuating a p53-dependent pathway.

Fibroblastic growth factor receptor 1 (FGFR1) signaling pathways are implicated in the regulation of FGF-23 gene transcription, but the molecular pathways remain poorly defined. We used low molecular weight (LMW, 18 kDa) FGF-2 and high molecular weight (HMW) FGF-2 isoforms, which, respectively, activate cell surface FGF receptors and intranuclear FGFR1, to determine the roles of membrane FGFRs and integrative nuclear FGFR1 signaling (INFS) in the regulation of FGF-23 gene transcription in osteoblasts. We found that LMW-FGF-2 induced NFAT and Ets1 binding to conserved cis-elements in the proximal FGF-23 promoter and stimulated FGF-23 promoter activity through PLCγ/calcineurin/NFAT and MAPK pathways in SaOS-2 and MC3T3-E1 osteoblasts. In contrast, HMW-FGF-2 stimulated FGF-23 promoter activity in osteoblasts through a cAMP-dependent binding of FGFR1 and cAMP-response element-binding protein (CREB) to a conserved cAMP response element (CRE) contiguous with the NFAT binding site in the FGF-23 promoter. Mutagenesis of the NFAT and CRE binding sites, respectively, inhibited the effects of LMW-FGF-2 and HMW-FGF-23 to stimulate FGF-23 promoter activity. FGF-2 activation of both membrane FGFRs and INFS-dependent FGFR1 pathways may provide a means to integrate systemic and local regulation of FGF-23 transcription under diverse physiological and pathological conditions.

Taurine, an intracellular osmolyte whose body pool size is adaptively regulated by the kidney, is required for normal renal development. Overexpression of the p53 tumor suppressor gene in p53 transgenic mice results in renal malformation, suggesting that altered expression of certain p53 target gene(s) involved in renal development may be responsible. This study shows that the taurine transporter gene (TauT) is a transcriptional target of p53. Expression of TauT was decreased after activation of p53 by doxorubicin, a DNA-damaging drug, in 293 and NRK-52E renal cells. TauT promoter activity was decreased 5-10-fold by cotransfection of a full-length TauT promoter-reporter construct with p53, which was reversed by cotransfection with a mutant p53 (p53-281). Electrophoretic mobility shift assays using nuclear extracts from p53-expressing (10)1val cells showed a putative p53-binding site in the TauT promoter region, which bound to the p53 in electrophoretic mobility shift assays. Mutation of this p53 consensus sequence abolished binding of p53. These results demonstrate that TauT may represent a downstream target gene of p53 that could link the roles of p53 in renal development and apoptosis.

Increases in fibroblastic growth factor 23 (FGF23 or Fgf23) production by osteocytes result in hypophosphatemia and rickets in the Hyp mouse homologue of X-linked hypophosphatemia (XLH). Fibroblastic growth factor (FGF) signaling has been implicated in the pathogenesis of Hyp. Here, we conditionally deleted FGF receptor 1 (FGFR1 or Fgfr1) in osteocytes of Hyp mice to investigate the role of autocrine/paracrine FGFR signaling in regulating FGF23 production by osteocytes. Crossing dentin matrix protein 1 (Dmp1)-Cre;Fgfr1 null/+ mice with female Hyp;Fgfr1 flox/flox mice created Hyp and Fgfr1 (Fgfr1Dmp1-cKO)-null mice (Hyp;Fgfr1 Dmp1-cKO) with a 70% decrease in bone Fgfr1 transcripts. Fgfr1Dmp1-cKO-null mice exhibited a 50% reduction in FGF23 expression in bone and 3-fold reduction in serum FGF23 concentrations, as well as reductions in sclerostin (Sost), phosphate regulating endopeptidase on X chromosome (PHEX or Phex), matrix extracellular phosphoglycoprotein (Mepe), and Dmp1 transcripts, but had no demonstrable alterations in phosphate or vitamin D homeostasis or skeletal morphology. Hyp mice had hypophosphatemia, reductions in 1,25(OH)2D levels, rickets/osteomalacia and elevated FGF2 expression in bone. Compared to Hyp mice, compound Hyp;Fgfr1 Dmp1-cKO-null mice had significant improvement in rickets and osteomalacia in association with a decrease in serum FGF23 (3607 to 1099 pg/ml), an increase in serum phosphate (6.0 mg/dl to 9.3 mg/dl) and 1,25(OH)2D (121±23 to 192±34 pg/ml) levels, but only a 30% reduction in bone FGF23 mRNA expression. FGF23 promoter activity in osteoblasts was stimulated by FGFR1 activation and inhibited by overexpression of a dominant negative FGFR1(TK−), PLCγ and MAPK inhibitors. FGF2 also stimulated the translation of an FGF23 cDNA transfected into osteoblasts via a FGFR1 and PI3K/Akt-dependent mechanism. Thus, activation of autocrine/paracrine FGF pathways is involved in the pathogenesis of Hyp through FGFR1-dependent regulation of FGF23 by both transcriptional and post-transcriptional mechanisms. This may serve to link local bone metabolism with systemic phosphate and vitamin D homeostasis.

Studies have demonstrated that TauT deficiency results in small kidneys in TauT knockout mice. Our studies have shown that TauT is a direct target of several genes, including p53 and WT1, which play an important role in renal development. However, whether the TauT gene is directly involved in renal development is largely unknown. In the present study, we created a TauT-deficient cell model by RNAi in human embryonic kidney 293 cells, and the effect of TauT on renal development was investigated. Knockdown of TauT significantly decreased the growth rate, cell migration, and colony formation of 293 cells. Inhibition of TauT caused cell cycle G2 arrest. Microarray analysis showed that several genes involved in cell cycle regulation or cell division, such as CDK6 and CDC7, were significantly downregulated in TauT-deficient 293 cells as compared to control 293 cells. In conclusion, the results from this study suggest that TauT plays a role in the development of renal cells. Knockdown of TauT impairs kidney development, possibly through regulation of cell cycle-related genes.

A postnatal role of fibroblast growth factor receptor-1 (FGFR1) in the kidney is suggested by its binding to α-Klotho to form an obligate receptor for the hormone fibroblast growth factor-23 (FGF-23). FGFR1 is expressed in both the proximal and distal renal tubular segments, but its tubular specific functions are unclear. In this study, we crossed Fgfr1flox/flox mice with either gamma-glutamyltransferase-Cre (γGT-Cre) or kidney specific-Cre (Ksp-Cre) mice to selectively create proximal tubule (PT) and distal tubule (DT) Fgfr1 conditional knockout mice (designated Fgfr1PT-cKO and Fgfr1DT-cKO, respectively). Fgfr1PT-cKO mice exhibited an increase in sodium-dependent phosphate co-transporter expression, hyperphosphatemia, and refractoriness to the phosphaturic actions of FGF-23, consistent with a direct role of FGFR1 in mediating the proximal tubular phosphate responses to FGF-23. In contrast, Fgfr1DT-cKO mice unexpectedly developed hypercalciuria, secondary elevations of parathyroid hormone (PTH), hypophosphatemia and enhanced urinary phosphate excretion. Fgfr1PT-cKO mice also developed a curly tail/spina bifida-like skeletal phenotype, whereas Fgfr1DT-cKO mice developed renal tubular micro-calcifications and reductions in cortical bone thickness. Thus, FGFR1 has dual functions to directly regulate proximal and distal tubule phosphate and calcium reabsorption, indicating a physiological role of FGFR1 signaling in both phosphate and calcium homeostasis.

Taurine participates in a number of different physiologic and biologic processes in the kidney, often reflected by urinary excretion patterns. The kidney is key to aspects of taurine body pool size and homeostasis. This review will examine the renal-taurine interactions relative to ion reabsorption; renal blood flow and renal vascular endothelial function; antioxidant properties, especially in the glomerulus; and the role of taurine in ischemia and reperfusion injury. In addition, taurine plays a role in the renal cell cycle and apoptosis, and functions as an osmolyte during the stress response. The role of the kidney in adaptation to variations in dietary taurine intake and the regulation of taurine body pool size are described. Finally, the protective function of taurine against several kidney diseases is reviewed.

The purpose of this study is to investigate the effect of taurine on the human fetal brain cells proliferation with the method of pure cerebral neuronal culture free of glial cells, grown in a serum-free environment. We found that taurine was necessary for neuronal survival, neurite extension. Taurine, on the other hand, has the trophic effect on the human fetal brain cells proliferation determined by [ 3 H]-thymidine incorporation. These results establish taurine as a putative human fetal brain neurontrophic factor in the process of human brain development.

Mammary epithelia produce an isotonic, low-Na+ fluid that is rich in nutrients. Mechanisms that account for the low electrolyte concentration have not been elucidated, although amiloride-sensitive ion transport has been reported in some situations. We hypothesized that corticosteroid exposure modulates epithelial Na+ channel (ENaC) expression and/or activity in bovine mammary epithelial cells. BME-UV cells were grown to confluent monolayers on permeable supports with a standard basolateral medium and apical medium of low-electrolyte, high-lactose composition that resembles the ionic composition of milk. Ion transport was assessed in modified Ussing flux chambers. Exposure to glucocorticoids (dexamethasone, cortisol, or prednisolone), but not aldosterone, increased short-circuit current ( Isc), a sensitive measure of net ion transport, whereas apical exposure to amiloride or benzamil reduced corticosteroid-induced Isc close to basal levels. Quantitative RT-PCR indicated a glucocorticoid-induced increase in mRNA for β- and γ-ENaC, whereas α-ENaC mRNA expression was only mildly affected. Exposure to mifepristone (a glucocorticoid receptor antagonist), but not spironolactone (a mineralocorticoid receptor antagonist), precluded both the corticosteroid-induced elevation in amiloride-sensitive Isc and the induced changes in β- and γ-ENaC mRNA. We conclude that Na+ movement across mammary epithelia is modulated by corticosteroids via a glucocorticoid receptor-mediated mechanism that regulates the expression of the β- and γ-subunits of ENaC. ENaC expression and activity could account for the low Na+ concentration that is typical of milk.

Cisplatin is a commonly used chemotherapeutic agent that has a major limitation because of its nephrotoxicity. Since cisplatin-induced renal injury is mainly confined to the S3 segment of renal proximal tubules-the primary site for renal adaptive regulation of TauT-we hypothesize that TauT functions as an anti-apoptotic gene and plays a role in protecting renal cells from drug-induced nephrotoxicity. In the present study we demonstrated that expression of TauT was significantly reduced by cisplatin (50 muM) in LLC-PK1 cells. Down-regulation of TauT by cisplatin occurs at the transcriptional level in a dose-dependent manner, as demonstrated through a reporter gene driven by the TauT promoter. It appears that cisplatin down-regulates TauT expression, at least in part, through the p53-dependent pathway, since cisplatin induces the p53 expression, which, in turn, represses TauT. Cisplatin induces apoptosis of LLC-PK1 cells in a dose-dependent manner. However, forced over-expression of TauT by stable transfection of a taurine transporter cDNA (pNCT) in LLC-PK1 cells was able to attenuate cisplatin-induced down-regulation of taurine uptake by LLC-PK1 cells and protect renal tubular cells from apoptosis. The mechanism by which TauT serves as an anti-apoptotic gene in cisplatin-induced renal injury remains to be determined, but could relate to taurine-dependent cell volume regulation.

In the present study we have demonstrated that WT1 (Wilms tumor suppressor gene) enhances the expression of TauT (taurine transporter gene) in human embryonic kidney 293 cells in a dose-dependent manner. TauT promoter activity was increased five-fold by cotransfection of a full-length TauT promoter–reporter construct with WT1. Electrophoretic mobility shift assays (EMSAs) using nuclear extracts from WT1-overexpressing 293 cells showed a putative WT1-binding site in the basal promoter region of TauT, which bound to WT1 in EMSAs. Mutation of this WT1 consensus sequence abolished binding of WT1. These results demonstrate that TauT may represent a downstream target gene of WT1 during renal development.

Taurine (2-aminoethanesulfonic acid) is primarily transported by its carrier, the taurine transporter, the gene for which has been cloned recently from several species and tissues 1–5. Expression of the taurine transporter gene (TauT) is regulated by many factors, including the p53 tumor suppressor gene, Wilms’ tumor suppressor gene (WT1), Sp1 transcription factor, and dietary taurine manipulation 6–9. In contrast, the taurine transporter itself, which contains 12 hydrophobic membrane-spanning domains, is mainly regulated by protein kinase C (PKC) phosphorylation 10. Our previous studies show that the fourth intracellular segment (S4) of the taurine transporter may be involved in the gating of taurine transport that is modulated by PKC phosphorylation of Ser-322 located in S4 11. In the present study, the role of charged amino acid residues located in S4 in the gating of taurine transport was determined using site-directed mutagenesis and the Xenopus laevis oocyte expression system.

The p53 tumor suppressor gene functions as a cell cycle checkpoint, blocking cell division in the G1 phase to allow repair of damaged DNA or even triggering apoptosis in cells that have defective genomes 1. Numerous stimuli trigger increases in the level of p53, including DNA-damaging drugs, ionizing radiation, ultraviolet light, and hypoxia 2–5. MCF-7, a human breast cancer estrogen receptor-positive (ER+) cell line, expresses a high level of wild-type p53, which is up-regulated by 17-s-estradiol (E2) 6. However, p53 function is largely inactivated in MCF-7 cells, caused by misallocation of p53 from nuclei to cytosol 7, which may result in the altered expression of certain p53 target genes. Studies have shown that the taurine transporter gene (TauT) is a putative target of p53 8, and that mutation of TauT results in severe and progressive retinal degeneration, a small brain, and shrunken kidneys 9. In the present study, we show that TauT is up-regulated by p53 and E2 in MCF-7 human breast cancer cells in a manner that appears to be mediated by estrogen receptor α (ERα).

Previous studies have shown that the Madin-Darby canine kidney cell taurine transporter (pNCT) is downregulated by protein kinase C (PKC) activation. In this study, it is hypothesized that the highly conserved serine-322 (Ser-322) located in the fourth intracellular segment (S4) may play an important role in the function of taurine transporter, which is modulated by PKC phosphorylation. It is demonstrated that Ser-322 is the critical site of PKC phosphorylation, as determined by site-directed mutagenesis. When Ser-322 of pNCT was changed to alanine (S322A) and this mutant was evaluated in an oocyte expression system, taurine transport activity increased threefold compared with control (wild-type pNCT). Activation of PKC by the active phorbol ester 12-myristate 13-acetate did not influence taurine transport by mutant S322A. Kinetic analysis showed that the mutation of Ser-322 essentially changed the Vmax, rather than the Km, of the transporter. Mutation of all other PKC consensus sites did not affect transporter activity when expressed in the oocyte system. Western blot analysis showed that expression of taurine transporter protein was similar in oocytes injected with either wild-type or mutant pNCT cRNA, indicating that the enhanced taurine transport activity by mutant S322A was not caused by a greater amount of transporter expressed in the oocyte. Furthermore, this study demonstrated that the taurine transporter was phosphorylated after PKC activation, and this effect was not observed in mutant S322A. In conclusion, Ser-322 is critical in PKC regulation of taurine transporter activity. The steady-state taurine transporter activity is tightly controlled by endogenous PKC phosphorylation of Ser-322, which is located in the fourth intracellular segment of the taurine transporter.

The purpose of this study was to investigate the effect of taurine on human fetal brain neuron cell proliferation and differentiation using a glial-free, pure cerebral neuronal culture grown in a serum-free environment. We found that taurine was necessary for neuronal survival and neurite extension. Taurine, on the other hand, has a trophic effect on the human fetal brain cell, promoting both proliferation and differentiation. Results showed that DNA synthesis of the neurons was increased in a dose-dependent manner when neurons were cultured in the medium containing taurine (100–6400 μM). The protein content of neuronal cells was also significantly increased in the neurons treated with taurine as compared to the control. At day 15, the expression of neuron-specific enolase (NSE) was only detected in the neurons cultured in the medium containing taurine. These results establish taurine as a putative human fetal brain neurontrophic factor in the process of human brain development.

Regulation of the taurine transporter gene in the S3 segment of the proximal tubule. Traditionally, bulk amino acid reabsorption in the kidney has been thought to be localized to the early portions of the proximal nephron. Adult Sprague-Dawley rats were fed diets with low, normal, and high taurine content for two weeks. Kidneys were hybridized with an 35S-radiolabeled complementary RNA probe to the rB16a subclone encoding the extracellular and transmembrane domains of the rat brain taurine transporter. Identical fragments were generated by RT-PCR from rat brain and kidneys as confirmed by DNA sequencing. Hybridization was localized to the outer zone of the medulla of all the kidneys. In the normal diet animals, taurine transporter mRNA was localized to the S3 segment of the proximal tubule, to the loop of Henle in the medulla, and to the glomerular epithelial cell layer. With taurine restriction, taurine transporter mRNA expression was up-regulated predominantly in the S3 segment and was virtually absent in this segment in animals supplemented with taurine. These experiments have precisely localized the rat kidney taurine transporter gene, demonstrating regulation that is limited to the S3 segment of the proximal tubule.

Background Cisplatin is a commonly used chemotherapeutic agent that has a major limitation because of its nephrotoxicity. We have demonstrated that cisplatin down-regulates the expression of the taurine transporter gene (TauT) in renal cells and that forced overexpression of TauT protects against cisplatin-induced apoptosis in renal cells in vitro and in vivo. In the present study, we have investigated how TauT is regulated by p53 and c-Jun and its role during acute kidney injury (AKI). Methods Regulation of TauT by p53 and c-Jun was determined by reporter gene assay, DNA binding, Western blot analysis, and immunohistochemistry. Results TauT was down-regulated by p53 and up-regulated by c-Jun. Two potential binding sites for c-Jun were identified in the promoter region of TauT. Inhibition of c-Jun N-terminal kinase (JNK) enhanced TauT promoter activity. Overexpression of TauT protects against cisplatin-induced kidney injury in a TauT transgenic mouse model. Conclusions Our findings suggest that TauT plays a critical role in renal function. Expression of TauT is negatively regulated by p53 and positively regulated by c-Jun, which is mediated by the JNK signaling pathway. The outcome level of TauT may determine the fate of renal cells during stress-induced AKI.