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Epigenetics play a role in the development of hypertension. However, the precise mechanisms of how histone modification in renal tubule cells regulates blood pressure is largely undiscovered. In this study, we investigated the role of renal Kdm6a in salt-sensitive hypertension using a kidney tubular cell-specific Kdm6a gene knockout (Kdm6a cKO) mouse model. First, we demonstrated that knockout of Kdm6a in the renal tubular cells resulted in an increase of H3K27me3 associated with the development of hypertension in both male and female Kdm6a cKO mice. To explore the mechanism of H3K27me3-mediated hypertension, we performed a ChIP seq to identify the target genes of H3K27me3 in the renal tubular cells. Data showed that H3K27me3 regulated several physiological pathways in the renal tubular cells, including sodium transport in proximal convoluted tubule (PCT), and blood pressure regulation in distal convoluted tubule (DCT). Indeed, we found that the expressions of NCC, NKCC2, and AQP2 were upregulated in kidneys of Kdm6a cKO mice. Furthermore, ChIP seq data reveals that FBLN2, an extracellular matrix protein, appears to be a target of H3K27me3, which was downregulated in the kidney of Kdm6a cKO mice determined by real-time PCR, Western, and IHC. Notably, we demonstrated that FBLN2 abated high salt-induced hypertension through downregulation of NCC, NKCC2, and AQP2 in the tubular cells of Kdm6a cKO mice. Interestingly, pre-treatment of FBLN2 prevented salt-sensitive hypertension in these mice. Additionally, we have provided evidence that FBLN2 may regulate blood pressure through mediating the NCC cell membrane trafficking. Using a super high-resolution microscopy, we demonstrated that FBLN2 reduced levels of cell surface NCC in DCT cells cultured in hypotonic medium. Here, we have first demonstrated that FBLN2 may be a target gene of H3K27me3 in epigenetic-mediated hypertension. FBLN2 treatment may prevent and treat salt-sensitive hypertension. NIH This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Aspergillus genus is a key component in fermentation and food processing. However, sterigmatocystin (STE)-a mycotoxin produced by several species of Aspergillus-limits the use of some Aspergillus species (such as Aspergillus versicolor, Aspergillus inflatus, and Aspergillus parasiticus) because of its toxicity and carcinogenicity. Here, we engineered an STE-free Aspergillus versicolor strain based on genome mining techniques. We sequenced and assembled the Aspergillus versicolor D5 genome (34.52 Mb), in which we identified 16 scaffolds and 54 biosynthetic gene clusters (BGCs). We silenced cytochrome P450 coding genes STC17 and STC27 by insertional inactivation. The production of STE in the Δstc17 mutant strain was increased by 282% but no STE was detected in the Δstc27 mutant. Metabolites of Δstc27 mutant exhibited growth-promoting effect on plants. Our study makes significant progress in improving the application of some Aspergillus strains by restricting their production of toxic and carcinogenic compounds.

Tobacco bacterial wilt caused by

Extracts from plants used in Chinese medicine can be good sources of fungicides for agricultural applications. In this study, we separated and identified antifungal compounds from four traditional Chinese medicine extracts and evaluated their antifungal activities in vitro and in vivo. In vitro, honokiol extracted from Artemisia argyi showed broad-spectrum antimicrobial and mycelial inhibitory activity with EC50 in the range 3.56 − 33.85 μg/mL against eight plant pathogens. q-PCR indicated that honokiol might induce cell cancerisation and inhibit cellular respiration, which provided significant insights into honokiol function in tobacco resistance to molecular mechanisms of the phytopathogenic fungus Phytophthora nicotianae. In vivo, honokiol significantly decreased the rate of fungal infection in eggplants, potatoes, grapes, cherry tomatoes, and cucumbers, and enhanced disease resistance in tobacco. Overall, our results indicate that honokiol has the potential to control a variety of fungal and oomycete diseases, and A. argyi could be a source of honokiol.

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.

KL (klotho) levels decline with age, which is an important mechanistic driver of aging. KL gene deficiency is associated with hypertension. The purpose of this study is to investigate the potential role of H3K27me3 (histone 3 lysine [K] 27 trimethylation) in the regulation of KL gene expression and examine the related molecular pathways that may drive kidney cell aging. Kidneys were collected from 6-month-old WT (wild type; young WT), 30-month-old WT (aged WT), and 6- (young) and 20-month-old (aged) KL mutant mice, respectively. We demonstrated that the H3K27me3 level was increased in kidneys of aged WT and KL mutant mice versus young WT mice. Elevation of H3K27me3 levels was likely due to downregulation of the H3K27 (histone H3 Lys 27)-specific demethylase JMJD3 (the Jumonji domain containing-3) in the aged kidneys. Inhibition of PRC2 (polycomb repressive complex C2; histone trimethyltransferase) decreased the H3K27me3 levels leading to an increase in the expression of KL in cultured primary renal tubule cells assessed by Western blot and KL promoter activity assays. The chromatin immunoprecipitation qPCR assay revealed that H3K27me3 was physically associated with the KL promoter region. Furthermore, aging impaired the SGK1 (serum- and glucocorticoid-induced protein kinase 1)/FOXO3a (the forkhead box class O 3a) signaling leading to upregulation of p53 and p16 (aging markers) in the kidney of aged WT mice. KL may regulate the SGK1/FOXO3 signaling, which was decreased due to KL deficiency. Thus, aging-associated downregulation of KL gene expression may be partly attributed to upregulation of H3K27me3 levels. Downregulation of KL may impair the SGK1/FOXO3 signaling contributing to kidney cell aging.

There is controversy regarding whether excess FGF23 causes left ventricular hypertrophy (LVH) directly through activation of fibroblast growth factor receptor 4 (FGFR4) in cardiomyocytes or indirectly through reductions in soluble Klotho (sK). We investigated the respective roles of myocardial FGFR4 and sKL in mediating FGF23-induced LVH using mouse genetic and pharmacological approaches. To investigate a direct role of myocardial FGFR4 in mediating the cardiotoxic effects of excess circulating FGF23, we administered rFGF23 to mice with cardiac-specific loss of FGFR4 (FGFR4 heart-cKO). We tested a model of sKL deficiency, hypertension and LVH created by the conditional deletion of FGFR1 in the renal distal tubule (FGFR1DT cKO mice). The cardioprotective effects of sKL in both mouse models was assessed by the systemic administration of recombinant sKL. We confirmed that FGF23 treatment activates PLCγ in the heart and induces LVH in the absence of membrane α-Klotho. Conditional deletion of FGFR4 in the myocardium prevented rFGF23-induced LVH in mice, establishing direct cardiotoxicity of FGF23 through activation of FGFR4. Recombinant sKL administration prevented LVH, but not HTN, in FGFR1DT cKO mice, consistent with direct cardioprotective effects. Co-administration of recombinant sKL with FGF23 in culture inhibited rFGF23-induced p-PLCγ signaling. Thus, FGF23 ability to include LVH represents a balance between FGF23 direct cardiac activation of FGFR4 and the modulating effects of circulating sKL to alter FGF23-dependent myocardial signaling pathways.

A novel bio-fertilizer, produced from prickly ash seeds (PAS), Bacillus subtilis and biochar, was evaluated for its disease-preventing potential on tobacco black shank caused by Phytophthora nicotianae. The results showed that biochar promoted the growth of Tpb55 in PAS and increased the pH of the organic fertilizer. The final concentration of B. subtilis could reach 1.7 × 1010 cfu g−1 in the biological organic fertilizer (PBB) under the optimal medium under conditions of solid-state fermentation. PBB exhibited a strong fumigation effect on P. nicotianae, including inhibiting mycelium growth, reducing the disease severity and decreasing the pathogen population in rhizospheric soil. PBB treatment also could significantly increase the pH of acidified soil and improve soil nutrition content such as available K, alkali hydrolysable N and organic carbon. High-throughput pyrosequencing of 16S and 18S rRNA genes revealed that 4% PBB addition in soil had significant effects on the diversity and richness of fungi but not on that of bacteria. The microbial community structure was also shifted after PBB treatment. Some potentially beneficial microbes such as Bacillus, Mucor, Cunninghamella, Chitinophaga and Phenylobacterium were enriched, while potential pathogen Fusarium was significantly decreased. In conclusion, the agricultural waste PAS combined with biochar can replace soybean as a source for the production of biocontrol B. subtilis Tpb55, and the novel bio-fertilizer could effectively control tobacco black shank by pathogen inhibition, soil nutrient improvement and shifting the rhizomicrobial community.

Recent studies have observed differing microbiomes between disease-suppressive and disease-conducive soils. However, it remains unclear whether the microbial keystone taxa in suppressive soil are critical for the suppression of diseases. Bacterial wilt is a common soil-borne disease caused by Ralstonia solanacearum that affects tobacco plants. In this study, two contrasting tobacco fields with bacterial wilt disease incidences of 0% (disease suppressive) and 100% (disease conducive) were observed. Through amplicon sequencing, as expected, a high abundance of Ralstonia was found in the disease-conducive soil, while large amounts of potential beneficial bacteria were found in the disease-suppressive soil. In the fungal community, an abundance of the Fusarium genus, which contains species that cause Fusarium wilt, showed a positive correlation (p < 0.001) with the abundance of Ralstonia. Network analysis revealed that the healthy plants had more complex bacterial networks than the diseased plants. A total of 9 and 13 bacterial keystone taxa were identified from the disease-suppressive soil and healthy root, respectively. Accumulated abundance of these bacterial keystones showed a negative correlation (p < 0.001) with the abundance of Ralstonia. To complement network analysis, culturable strains were isolated, and three species belonging to Pseudomonas showed high 16S rRNA gene similarity (98.4–100%) with keystone taxa. These strains displayed strong inhibition on pathogens and reduced the incidence of bacterial wilt disease in greenhouse condition. This study highlighted the importance of keystone species in the protection of crops against pathogen infection and proposed an approach to obtain beneficial bacteria through identifying keystone species, avoiding large-scale bacterial isolation and cultivation.

Objective: Aging-associated downregulation of Klotho is partly due to epigenetic upregulation of H3K27me3 in the kidney. The purpose of this study is to investigate the potential role of KDM6a, a demethylase of histone 3 lysine (K) 27 trimethylation (H3K27me3), in the regulation of blood pressure and explore the related molecular pathways that may influence the kidney function during aging. Methods and Results: Wild type and Ksp-Cre/KDM6a-floxed mice were divided into vehicle control and tamoxifen (10 mg/kg/mouse/7days) treated cohorts (WT mice: KDM6a floxed or Ksp-Cre only and Ksp-Cre/KDM6a -loxed mice). Blood pressure (BP) was measured by tail cuff method and confirmed by carotid artery cannulation at the end of study. Deletion of the KDM6a gene (KDM6a-cKO) significantly increased BP at day 7. BP remained elevated throughout the study. We found that the H3K27me3 level was significantly increased in the kidneys of KDM6a-cKO mice compared to control mice confirming that KDM6a is an important H3K27 demethylase in the control of methylation levels in the kidney. Elevation of BP was likely due to upregulation of the Na + :K + :2Cl - co-transporter (NKCC2) in the thick ascending limb of Henle's loop and NaCl co-transporter (NCC) in the distal convoluted tubule confirmed by qPCR and immunohistochemistry. Accordingly, we found that the urine sodium level was decreased in KDM6a-cKO mice compared to KDM6a-con mice. We showed that expression of aquaporin 2 (AQP2) was increased in the kidney of KDM6a-cKO mice, suggesting that AQP2 may also contribute to increased BP through modulation of body water homeostasis. Furthermore, we demonstrated that expression of Klotho was downregulated by 50%, which blocked FGFR1/Klotho/ERK signaling in the kidney of KDM6a-cKO mice. Notably, expression of aging markers including p53, p21, and p16 was significantly increased in the kidney of KDM6a-cKO mice, indicating that deletion of KDM6a in the renal tubule results in kidney aging. Conclusion: KDM6A is essential to the maintenance of normal kidney function and blood pressure. Renal-specific KDM6A knockout-induced hypertension is likely attributed to increased H3K27me3 levels and the resultant dowregulation of Klotho gene expression which impairs the FGFR1/Klotho/ERK signaling.

Diatomite is a kind of natural material with adsorption capacity and it’s widely used in industry. The main purpose of this paper is to study the influence of hydrochloric acid concentration and modification time on the modification effect of diatomite. This article describes a modified method of diatomite, which can not only reduce the purification cost, but also improve the separation efficiency of solanesol. The results show that when the concentration of hydrochloric acid is 3mol/L and the treatment time is 50 minutes, the modification effect of diatomite is the best. The determination of the optimum technological conditions is conducive to the separation and purification of Solanesol by diatomite, and lays a foundation for the further development and utilization of diatomite.

Paenibacillus polymyxa is an important member of the plant growth-promoting rhizobacteria. P. polymyxa YC0136 inoculation had beneficial effect on growth promotion and biological control of tobacco (Nicotiana tabacum L.) under field conditions. This study aimed to reveal the growth-promoting mechanisms of strain YC0136. In growth-promotion assays, tobacco plant height was increased by 8.42% and 8.25% at 60 and 90 days, respectively, after inoculation with strain YC0136. Strain YC0136 also promoted the accumulation of tobacco biomass in varying degrees. Following inoculation with strain YC0136, 3,525 and 4,368 tobacco genes were up-regulated and down-regulated, respectively. Strain YC0136 induced the expression of plant hormone-related genes in tobacco, including auxin, cytokinin, and gibberellin, as well as transcription factors related to stress resistance such as WRKY and MYB. In addition, strain YC0136 induced the up-regulation of genes in the phenylpropanoid biosynthesis pathway by 1.51–4.59 times. Interaction with tobacco also induced gene expression changes in strain YC0136, with 286 and 223 genes up-regulated and down-regulated, respectively. Tobacco interaction induced up-regulation of the ilvB gene related to auxin biosynthesis in strain YC0136 by 1.72 times and induced expression of some nutrient transport genes. This study contributes to our understanding of the growth-promoting mechanisms of strain YC0136 on tobacco and provides a theoretical basis for the application of P. polymyxa YC0136 as a biological fertilizer.

This study explored the chemical compositions of garlic essential oil, the inhibitory activity of garlic essential oil and diallyl disulfide (DADS) against Phytophthora nicotianae, and the effects on mycelial plasma membrane permeability and P. nicotianae inhibition. In total, 29 compounds were detected in garlic essential oil, of which 26 were detected by gas chromatography‒mass spectrometry (GC-MS) and 21 by headspace solid-phase microextraction (HS-SPME) GC-MS. DADS (60.12% and 19.09%) and trisulfide di-2-propenyl (14.18% and 17.98%) were the major components identified by HS-SPME GC-MS and GC-MS analysis, respectively. Half-inhibitory concentration (Ec50, antagonism) and minimum inhibitory concentration (MIC, fumigation) of DADS against P. nicotianae were 150.83 &mu, L/L and 20 &mu, L/L, respectively, while Ec50 of garlic essential oil was 1108.25 &mu, L/L. Mycelial membrane permeability gradually increased in a concentration-dependent manner, and cell death increased at 450 &mu, L/L DADS. Furthermore, DADS treatment significantly reduced the incidence of tobacco black shank and the number of P. nicotianae pathogens in rhizosphere soil. DADS also promoted root development of tobacco seedlings at low concentrations, which was inhibited at high concentrations. Therefore, DADS may play an important role in the antifungal effect against P. nicotianae by destroying mycelial cell membrane integrity, causing an increase in cell membrane permeability, and leading to cell death.

Two novel 3-decalinoyltetramic acid (3DTA) derivatives, namely fusarisetins C and D (1 and 2), and four known derivatives (3–6) were isolated from the marine-derived fungus Fusarium equiseti D39. Their structures were determined by spectroscopic data, vibrational circular dichroism (VCD) calculations, and X-ray crystallography. Compound 2 was identified as the first fusarisetin to possess an unprecedented carbon skeleton with a tetracyclic ring system comprised of a decalin moiety (6/6) and a tetramic acid moiety. A plausible biosynthetic pathway for the isolated compounds was proposed. All 3DTAs derivatives exhibited a potent phytotoxicity, and 5 also displayed a remarkable anti-phytopathogenic activity superior to the positive control resulting in damage of the cell membrane of Pseudomonas syringae and ensuing leakage of the intracellular components. Here, the phytotoxicity of fusarisetins has been reported for the first time. The OSMAC fermentation optimization approach to give 5 was performed by varying the culture media and salinities. The results showed that potato liquid medium with 1% salinity is the most favorable condition for the production of 5.

Bacillus velezensis DSYZ is a plant growth-promoting rhizobacterium with the capacity to control fungal pathogens. It was isolated from the rhizosphere soil of garlic., Bacillus velezensis DSYZ is a plant growth-promoting rhizobacterium with the capacity to control fungal pathogens. It was isolated from the rhizosphere soil of garlic. Here, we present the complete genome sequence of B. velezensis DSYZ. Several gene clusters that are related to the biosynthesis of antimicrobial compounds were predicted.

The regeneration and reusing of reclaimed asphalt mixture can promote the recycling of waste building materials and the sustainable development of asphalt pavement. To further improve the properties of rejuvenated SBS modified asphalt, the effects of structural changes of SBS, and the colloidal stability of asphalt on the properties of binder were studied. And based on the results, bio-rejuvenator and active rejuvenator were applied to rejuvenate ultraviolet aged SBS modified asphalt (USMA), the impacts of rejuvenators on the composition, structure, physical and rheological properties of USMA were systematically investigated. The results show the decrease of colloidal index and the damage of SBS structure all have a serious adverse influence on the properties of binder. Bio-rejuvenator can rebalance the colloidal stability of ultraviolet (UV) aged binders, meanwhile active rejuvenator could react with the active terminal groups of broken SBS segments and partially rebuilds its crosslinking structure. And the physical and rheological properties of UV aged asphalt can be all basically restored by adding bio-rejuvenator; however bio-rejuvenator cannot restore the properties of USMA, which can only improve the low-temperature performance of USMA. While the addition of active rejuvenator greatly enhances the high-temperature performance of rejuvenated SBS modified asphalt. Furthermore, the combination of bio-rejuvenator and active rejuvenator can both recover the colloidal structure and damaged SBS structure of USMA, which obviously improves its high- and low-temperature properties overall. This paper would contribute to the realization of high-quality regeneration of reclaimed SBS modified asphalt.

To fully restore the performance of waste SBS modified asphalt mixture, better realize its recycling and application in high-grade pavement, achieve the concept of sustainable green development of asphalt pavement. In this paper, the synergistic effects of bio-rejuvenator and active isocyanate rejuvenators (including hexamethylene diisocyanate (HDI), diphenyl-methane-diisocyanate (MDI) and toluene-2, 6-diisocyanate (TDI)) on the chemical structure, physical and rheological properties of aged SBS modified bitumen were thoroughly investigated. Fourier infrared spectrum and Gel permeation chromatography analysis indicate the isocyanate groups of active rejuvenators react with hydroxyl or carboxyl group from the degraded SBS segments to form new amide groups that can reconnect the broken segments of aged SBS and partly restore its molecular weight distribution. From physical and rheological properties, bio-rejuvenator can restore the low-temperature properties by rebalancing the colloidal structure of aged binder, meanwhile, active rejuvenators can greatly improve the high-temperature performance of rejuvenated SBS modified bitumen with bio-rejuvenator through reconnecting the broken segments of aged modifier SBS. Furthermore, MDI with benzene ring structure is more conducive to enhancing the high temperature rutting resistance of rejuvenated SBS modified bitumen. While HDI can bring some flexible segments into the restored structure of SBS, which is more beneficial to improve its low-temperature cracking resistance of rejuvenated binder. And the fluorescence images further demonstrate isocyanate rejuvenators can partly restore the crosslinking network structure of aged modifier SBS in rejuvenated SBS modified bitumen. This research would be conductive to promoting the application of rejuvenated SBS modified bitumen into the construction of high standard pavement.

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.

High-purity solanesol can be used for pharmaceutical applications, but the current method for purifying solanesol has high cost and difficult continuous operation, and the use of molecular imprinting to purify natural products is a hot research topic of current research. Solanesol molecularly imprinted polymers were synthesized via emulsion polymerization for the first time. The morphology of the SSO-MIPs was observed with a scanning electron microscope, and the effects of the synthesis time, initiator dosage, functional monomer dosage, and cross-linking agent dosage on the adsorption effects under high-temperature and rapid synthesis conditions were discussed. The results demonstrate that the optimum synthesis conditions were a ratio of the template molecules to the functional monomers to the cross-linking agents of 1:8:30 (mol:mol:mol), 10 mg of the initiator, and a synthesis temperature of 70 &deg, C. The imprinting factor of SSO-MIPs synthesized under the optimized process was found to reach 2.51, and the SSO-MIPs synthesized by this method exhibited a good adsorption effect, emitted less pollution during the synthesis process, and are convenient for demulsification. This research reports a reliable method for the synthesis of solanesol molecularly imprinted polymers.

Both the activation of the renin angiotensin aldosterone system (RAAS) and elevations of circulating Fibroblast Growth Factor-23 (FGF-23) have been implicated in the pathogenesis of left ventricular hypertrophy (LVH) in chronic kidney disease. To investigate potential cross-talk between RAAS and FGF-23, we administered angiotensin II (Ang II) to wild-type rodents and the Hyp mouse model of excess FGF-23. Ang II administration for four weeks to wild-type rodents resulted in significant increases in systolic blood pressure and LVH. Unexpectedly, FGF-23 circulating levels were increased by 1.5–1.7 fold in Ang II treated animals. In addition, Ang II treatment increased expression of FGF-23 message levels in bone, the predominant tissue for FGF-23 production, and induced expression of FGF-23 and its co-receptor α-Klotho in the heart, which normally does not express FGF-23 or α-Klotho in physiologically relevant levels. Hyp mice with elevated FGF-23 exhibited increased blood pressure and LVH at baseline. Ang II administration to Hyp mice resulted further increments in blood pressure and left ventricular hypertrophy, consistent with additive cardiovascular effects. These findings suggest that FGF-23 may participate in unexpected systemic and paracrine networks regulating hemodynamic and myocardial responses.

Fibroblast growth factor-23 (FGF-23) is a bone-derived hormone that activates FGFR/α-Klotho binary complexes in the kidney renal tubules to regulate phosphate reabsorption and vitamin D metabolism. The objective of this review is to discuss the emerging data that show that FGF-23 has functions beyond regulation of mineral metabolism, including roles in innate immune and hemodynamic responses. Excess FGF-23 is associated with inflammation and adverse infectious outcomes, as well as increased morbidity and mortality, particularly in patients with chronic kidney disease. Enhancer elements in the FGF-23 promoter have been identified that mediate the effects of inflammatory cytokines to stimulate FGF-23 gene transcription in bone. In addition, inflammation induces ectopic expression of FGF-23 and α-Klotho in macrophages that do not normally express FGF-23 or its binary receptor complexes. These observations suggest that FGF-23 may play an important role in regulating innate immunity through multiple potential mechanisms. Circulating FGF-23 acts as a counter-regulatory hormone to suppress 1,25D production in the proximal tubule of the kidney. Since vitamin D deficiency may predispose infectious and cardiovascular diseases, FGF-23 effects on innate immune responses may be due to suppression of 1,25D production. Alternatively, systemic and locally produced FGF-23 may modulate immune functions through direct interactions with myeloid cells, including macrophages and polymorphonuclear leukocytes to impair immune cell functions. Short-acting small molecules that reversibly inhibit FGF-23 offer the potential to block pro-inflammatory and cardiotoxic effects of FGF-23 with less side effects compared with FGF-23 blocking antibodies that have the potential to cause hyperphosphatemia and soft tissue calcifications in animal models. In conclusion, there are several mechanisms by which FGF-23 impacts the innate immune system and further investigation is critical for the development of therapies to treat diseases associated with elevated FGF-23.

The bone-derived hormone fibroblast growth factor-23 (FGF-23) activates complexes composed of FGF receptors (FGFRs), including FGFR1, and α-Klotho in the kidney distal tubule (DT), leading to increased sodium retention and hypertension. However, the role of FGFR1 in regulating renal processes linked to hypertension is unclear. Here, we investigated the effects of selective FGFR1 loss in the DT. Conditional knockout (cKO) of FGFR1 in the DT (FGFR1DT-cKO mice) resulted in left ventricular hypertrophy (LVH) and decreased kidney expression of α-Klotho in association with enhanced BP, decreased expression of angiotensin converting enzyme 2, and increased expression of the Na+-K+-2Cl- cotransporter. Notably, recombinant FGF-23 administration similarly decreased the kidney expression of α-Klotho and induced LVH in mice. Pharmacologic activation of FGFR1 with a monoclonal anti-FGFR1 antibody (R1MAb1) normalized BP and significantly attenuated LVH in the Hyp mouse model of excess FGF-23, but did not induce a response in FGFR1DT-cKO mice. The hearts of FGFR1DT-cKO mice showed increased expression of the transient receptor potential cation channel, subfamily C, member 6 (TRPC6), consistent with cardiac effects of soluble Klotho deficiency. Moreover, administration of recombinant soluble Klotho lowered BP in the Hyp mice. Thus, FGFR1 in the DT regulates systemic hemodynamic responses opposite to those predicted by the actions of FGF-23. These cardiovascular effects appear to be mediated by paracrine FGF control of kidney FGFR1 and subsequent regulation of soluble Klotho and TRPC6. FGFR1 in the kidney may provide a new molecular target for treating hypertension.

Serum levels of fibroblast growth factor 23 (FGF23) markedly increase with renal impairment, with FGF23 levels correlating with the presence of left ventricular hypertrophy (LVH) and mortality in patients with chronic kidney disease (CKD). FGF23 activates calcineurin/nuclear factor of activated T cell (NFAT) signaling and induces hypertrophy in murine cardiomyocytes. X-linked hypophosphatemia (XLH) is characterized by high circulating levels of FGF23 but, in contrast to CKD, is associated with hypophosphatemia. The cardiac effects of high circulating levels of FGF23 in XLH are not well defined. Thus, studies were undertaken to define the cardiac phenotype in the mouse model of XLH (Hyp mice). Echocardiographic and histological analyses demonstrated that Hyp left ventricles (LVs) are smaller than those of wild-type mice. Messenger RNA expression of cardiac hypertrophy markers was not altered in the LV or right ventricle of Hyp mice. However, the Hyp LVs had increased expression of the NFAT target genes NFATc1 and RCAN1. To determine whether phosphate alone can induce markers of hypertrophy, differentiated C2C12 myocytes were treated with phosphate. Phosphate treatment increased expression of cardiac hypertrophy markers, supporting a primary role for phosphate in inducing LVH. Although previous studies showed that increased circulating FGF23 and phosphate levels are associated with LVH, our results demonstrated that in XLH, high circulating levels of FGF23 in the setting of hypophosphatemia do not induce cardiac hypertrophy.

A healthy 37-year-old woman developed delirium and was comatose on admission after a 3-day history of chills, fever, and myalgias. Neuroimaging showed lesions affecting bilateral thalami and pons (figures 1 and 2) and normal venous sinuses. Laboratory tests detected elevated serum aminotransferases, increased CSF protein, and no specific virus (tables e-1–e-3, [links.lww.com/WNL/A597][1]). She gradually recovered consciousness in 4 days, maintained left-sided 1/5 plegia and slurred speech, and was discharged 28 days later (NIH Stroke Scale score 2). [1]: http://links.lww.com/WNL/A597

Calcium has recently been shown to regulate fibroblast growth factor 23 (FGF-23), a bone-derived phosphate and vitamin D-regulating hormone. To better understand the regulation of FGF-23 by calcium, phosphorus, 1,25 dihydroxyvitamin D3 [1,25(OH)2D], and PTH, we examined FGF-23 expression under basal conditions and in response to PTH, doxercalciferol, or high-calcium diet treatment in Gcm2−/− and Cyp27b1−/− mutant mice. Gcm2−/− mice exhibited low serum PTH and 1,25(OH)2D concentrations, hypocalcemia, and hyperphosphatemia, whereas Cyp27b1−/− mice had high PTH, undetectable 1,25(OH)2D, hypocalcemia, and hypophosphatemia. Serum FGF-23 levels were decreased in both mutant models. Doxercalciferol administration increased serum FGF-23 levels in both mutant models. PTH administration to Gcm2−/− mice also increased serum FGF-23 levels, in association with an increase in both 1,25(OH)2D and calcium concentrations. Multiple regression analysis of pooled data indicated that changes in FGF-23 were positively correlated with serum calcium and 1,25(OH)2D but not related to changes in serum phosphate concentrations. A high-calcium diet also increased serum FGF-23 concentrations in Cyp27b1−/− mice in the absence of 1,25(OH)2D and in Gcm2−/− mice with low PTH. The addition of calcium to the culture media also stimulated FGF-23 message expression in MC3T3-E1 osteoblasts. In addition, FGF-23 promoter activity in cultured osteoblasts was inhibited by the L-calcium-channel inhibitor nifedipine and stimulated by calcium ionophores. The effects of chronic low calcium to prevent 1,25(OH)2D and PTH stimulation of FGF-23 in these mutant mouse models suggest that suppression of FGF-23 plays an important physiological adaptive response to hypocalcemia.

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.