FGF23-Klotho signaling axis in the kidney

AbstractFibroblast growth factor-23 (FGF23) is a bone-derived hormone protecting against the potentially deleterious effects of hyperphosphatemia by suppression of phosphate reabsorption and of active vitamin D hormone synthesis in the kidney. The kidney is one of the main target organs of FGF23 signaling. The purpose of this review is to highlight the recent advances in the area of FGF23-Klotho signaling in the kidney. During recent years, it has become clear that FGF23 acts independently on proximal and distal tubular epithelium. In proximal renal tubules, FGF23 suppresses phosphate reabsorption by a Klotho dependent activation of extracellular signal-regulated kinase-1/2 (ERK1/2) and of serum/glucocorticoid-regulated kinase-1 (SGK1), leading to phosphorylation of the scaffolding protein Na+/H+ exchange regulatory cofactor (NHERF)-1 and subsequent internalization and degradation of sodium-phosphate cotransporters. In distal renal tubules, FGF23 augments calcium and sodium reabsorption by increasing the apical membrane expression of the epithelial calcium channel TRPV5 and of the sodium-chloride cotransporter NCC through a Klotho dependent activation of with-no-lysine kinase-4 (WNK4). In proximal and distal renal tubules, FGF receptor-1 is probably the dominant FGF receptor mediating the effects of FGF23 by forming a complex with membrane-bound Klotho in the basolateral membrane. The newly described sodium- and calcium-conserving functions of FGF23 may have major implications for the pathophysiology of diseases characterized by chronically increased circulating FGF23 concentrations such as chronic kidney disease

Bone loss in KLHL3 knock-in mice characterized by a pseudohypoaldosteronism type II-like phenotype is mediated by renal PTH resistance

This is the final versionPoster presented at the 43rd Annual European Calcified Tissue Society Congress, Rome, Italy, 14 - 17 May 2016Pseudohypoaldosteronism type II (PHAII) is a hereditary disease characterized by hypertension, hypercalciuria and osteopenia. PHAII is caused by mutations in with-no-lysine kinase 1 (WNK1), WNK4, or the cullin RING ligase family members kelch-like 3 (KLHL3) or cullin 3 (CUL3). All mutations result in up-regulation of the WNK signalling pathway which activates thiazide-sensitive Na-Cl cotransporters (NCC) in renal distal tubules, leading to salt retention and hypertension in PHAII. The mechanism underlying hypercalciuria in PHAII is unknown. To better understand the mechanisms leading to osteopenia in PHAII, we used KLHL3R528H/+ knock-in mice carrying the same mutation as some PHAII patients. As expected, KLHL3R528H/+ mutants exhibited hyperkalemia, hypernatremia, renal calcium wasting and increased phosphorylation of NCC in the kidney. Furthermore, KLHL3R528H/+ mutants showed elevated serum parathyroid hormone (PTH), increased bone resorption as demonstrated by elevated urinary collagen crosslinks excretion and increased osteoclast numbers in femoral cancellous bone, and reduced distal femoral cancellous bone BMD and volume as evidenced by pQCT and μCT analysis. Analysis of the expression of proteins involved in renal calcium transport revealed elevated membrane abundance of the fully glycosylated epithelial calcium channel TRPV5, decreased TRPV6 abundance, and unchanged calbindin D28k expression in KLHL3R528H/+ mutants. In contrast to the upregulated TRPV5 protein expression, TRPV5 phosphorylation was reduced in KLHL3R528H/+ mutants, suggesting downregulated TRPV5 activity. In line with a crosstalk between NCC activity and PTH-mediated TRPV5 activation, we found by 2-photon microscopy that the PTH-mediated increase in Ca2+ uptake in mouse distal tubular mpkDCT4 cells was enhanced by the NCC blocker chlorothiazide or by knockout of NCC. Taken together, our study provides a mechanistic explanation for the hypercalciuria and bone loss found in PHAII patients: elevated NCC activity in KLHL3R528H/+ mice blocks PTH-mediated TRPV5 activation, leading to renal PTH resistance with subsequent renal Ca wasting and a counter-regulatory PTH-induced bone loss

Prognostic importance of plasma total magnesium in a cohort of cats with azotemic chronic kidney disease

BACKGROUND: Hypomagnesemia is associated with increased mortality and renal function decline in humans with chronic kidney disease (CKD). Magnesium is furthermore inversely associated with fibroblast growth factor 23 (FGF23), an important prognostic factor in CKD in cats. However, the prognostic significance of plasma magnesium in cats with CKD is unknown. OBJECTIVES: To explore associations of plasma total magnesium concentration (tMg) with plasma FGF23 concentration, all-cause mortality, and disease progression in cats with azotemic CKD. ANIMALS: Records of 174 client-owned cats with IRIS stage 2-4 CKD. METHODS: Cohort study. Cats with azotemic CKD were identified from the records of two London-based first opinion practices (1999-2013). Possible associations of baseline plasma tMg with FGF23 concentration and risks of death and progression were explored using, respectively, linear, Cox, and logistic regression. RESULTS: Plasma tMg (reference interval, 1.73-2.57 mg/dL) was inversely associated with plasma FGF23 when controlling for plasma creatinine and phosphate concentrations (partial correlation coefficient, -0.50; P < .001). Hypomagnesemia was observed in 12% (20/174) of cats, and independently associated with increased risk of death (adjusted hazard ratio, 2.74; 95% confidence interval [CI], 1.35-5.55; P = .005). The unadjusted associations of hypermagnesemia (prevalence, 6%; 11/174 cats) with survival (hazard ratio, 2.88; 95% CI, 1.54-5.38; P = .001), and hypomagnesemia with progressive CKD (odds ratio, 17.7; 95% CI, 2.04-154; P = .009) lost significance in multivariable analysis. CONCLUSIONS AND CLINICAL IMPORTANCE: Hypomagnesemia was associated with higher plasma FGF23 concentrations and increased risk of death. Measurement of plasma tMg augments prognostic information in cats with CKD, but whether these observations are associations or causations warrants further investigation

Oilfield service companies as part of economy digitalization: assessment of the prospects for innovative development

The digital transformation of the economy as the most important stage of scientific and technological progress and transition to a new technological structure is becoming one of the determining factors in the development and competitiveness of the domestic upstream sector. Prospects for innovative development of oilfield service companies are the key technological areas within the first project of the Hi-Tech Strategy of the German Government until 2020 – “Industry 4.0”. The purpose of this study is to assess the prospects for innovative development of the domestic oilfield service industry in the context of the digitalization of the oil and gas industry. The subject of the research is the process of the formation of key technological lines of “Industry 4.0” and their impact on the domestic oil and gas sector. The research is based on logical-theoretical and empirical analyses. The main factors that determine processes of digital transformation in the oil and gas industry are considered; the results of digitalization processes in the largest foreign and Russian industry companies of the upstream and oilfield services segments are presented. The information base is made up of data from oilfield service and oil and gas producing companies, presented on the official websites of companies in the public domain on the Internet. It has been proven that, unlike the world's leading companies in oilfield services segment, independent domestic oilfield service companies provide mainly traditional service technologies in a fairly narrow range. The limited scope of functioning and technological capabilities of Russian companies is explained by the lack of necessary investment in development and expansion of business, as well as interest on the part of the state and corporate sectors in the development and replication of domestic technologies and the formation of a full-fledged oilfield services market in Russia

Toolkit for Simulation Modeling of Logistics Warehouse in Distributed Computing Environment

We address an important problem of an automation of logistics warehouses simulation modeling in distributed service-oriented computing environments. To this end, we propose new approach for adjusting management system parameters of real warehouse in production use. It is based on the integration of the conceptual, wireframe and service-oriented programming used to develop parameter sweep applications and data analysis in the simulation modeling process. We develop a toolkit for supporting modeling of warehouse logistics. The practical experiments are focused upon the refrigerated warehouse. The developed application demonstrates high efficiency and scalability for optimizing nine criteria to cope with different production demands.The study was supported by the Russian Foundation of Basic Research, projects no. 15-29-07955 and no. 16-07-00931, and Program 1.33P of fundamental research of Presidium RAS, project “Development of new approaches to creation and study of complex models of information-computational and dynamic systems with applications”

Новый азотсодержащий полимер с упрочняющим и гидрофобизирующим действием на бумагу и картон

A new nitrogen-containing product based on tall oil rosin, adipic acid and diethylenetriamine is capable of simultaneously exerting a strengthening and hydrophobizing effect on paper and cardboard made both from primary (cellulose) and secondary (waste paper) fibers. The strengthening effect is due to the presence in its structure of nitrogen-containing groups –NH2 and –NH– capable of forming additional interfiber bonds with negatively charged hydroxyl groups of cellulose macromolecules. Hydrophobizing effect is provided by resin acids included in the product. Preparation of the product with preset physicochemical properties (acid number not more than 40 mg KOH/g, solubility in water, cationic character and thermal stability at a temperature of at least 135 °C) was carried out in three stages. The first stage is the tall oil resin acids modification with diethylenetriamine; the second stage is the polycondensation of the resin acid amides obtained in the first stage with adipic acid and diethylenetriamine; the final stage is water dilution of the product formed in the second stage, to a solids content of 10–12 %. In paper masses containing primary and secondary fibers glued with alkylketene dimers (Fennosize KD 225 YP), the replacement of the import strengthening agent (cationic starch Hi-Cat) with a new nitrogen-containing product allows us, first, to increase the dry strength of paper and cardboard and improve hydrophobicity and, secondly, to prevent undesirable process of “sticking” when storing paper samples (elementary layers of cardboard).Новый азотсодержащий полимер на основе талловой канифоли, адипиновой кислоты и диэтилентриамина способен одновременно оказывать упрочняющее и гидрофобизирующее действие на бумагу и картон, изготовленные как из первичных волокон (целлюлозных), так и вторичных (макулатурных). Упрочняющее действие обусловлено наличием в его структуре азотсодержащих групп –NH2 и –NH–, способных образовывать дополнительные межволоконные связи с отрицательно заряженными гидроксильными группами макромолекул волокон. Гидрофобизирующее действие обеспечивают смоляные кислоты, входящие в состав продукта. Получение продукта с заданными физико-химическими свойствами (кислотное число не более 40 мг KOH/г, растворимость в воде, катионный характер, термическая стабильность при температуре не менее 135 °С) осуществляли в три стадии: 1 – модифицирование смоляных кислот талловой канифоли диэтилентриамином; 2 – поликонденсация амидов смоляных кислот канифоли, полученных на первой стадии, с адипиновой кислотой и диэтилентриамином; 3 – разведение продукта, образовавшегося на второй стадии, водой до содержания сухих веществ 10–12 %. В бумажных массах, проклеенных димерами алкилкетенов (например, Fennosize KD 225 YP), осуществляется замена импортного упрочняющего вещества (катионного крахмала Hi-Cat) на новый азотсодержащий продукт, что позволяет, во-первых, увеличить прочность образцов бумаги и картона в сухом состоянии и улучшить их гидрофобность и, во-вторых, предотвратить нежелательный процесс «расклейки» при их хранении

Fibroblast growth factor 23 is related to profiles indicating volume overload, poor therapy optimization and prognosis in patients with new-onset and worsening heart failure

Background: Fibroblast growth factor (FGF) 23 is a hormone that increases urinary phosphate excretion and regulates renal sodium reabsorption and plasma volume. We studied the role of plasma FGF23 in therapy optimization and outcomes in patients with new-onset and worsening heart failure (HF). Methods: We measured plasma C-terminal FGF23 levels at baseline in 2399 of the 2516 patients included in the BIOlogy Study to Tailored Treatment in Chronic HF (BIOSTAT-CHF) trial. The association between FGF23 and outcome was evaluated by Cox regression analysis adjusted for potential confounders. Results: Median FGF23 was 218.0 [IQR: 117.1–579.3] RU/ml; patients with higher FGF23 levels had a worse NYHA class, more signs of congestion, and were less likely to use an ACE-inhibitor (ACEi) or angiotensin receptor blocker (ARBs) at baseline (all P &lt; 0.01). Higher FGF23 levels were independently associated with higher BNP, lower eGFR, the presence of oedema and atrial fibrillation (all P &lt; 0.001). In addition, higher FGF23 was independently associated with impaired uptitration of ACEi/ARBs after 3 months, but not of beta-blockers. In multivariable Cox regression analysis, FGF23 was independently associated with all-cause mortality (hazard ratio: 1.17 (1.09–1.26) per log increase, P &lt; 0.001), and the combined endpoint of all-cause mortality and HF hospitalization (1.15 (1.08–1.22) per log increase, P &lt; 0.001). Conclusions: In patients with new-onset and worsening HF, higher plasma FGF23 levels were independently associated with volume overload, less successful uptitration of ACEi/ARBs and an increased risk of all-cause mortality and HF hospitalization

Klotho Lacks a Vitamin D Independent Physiological Role in Glucose Homeostasis, Bone Turnover, and Steady-State PTH Secretion In Vivo

Apart from its function as co-receptor for fibroblast growth factor-23 (FGF23), Klotho is thought to regulate insulin signaling, intracellular oxidative stress, and parathyroid hormone (PTH) secretion in an FGF23 independent fashion. Here, we crossed Klotho deficient (Kl−/−) mice with vitamin D receptor (VDR) mutant mice to examine further vitamin D independent functions of Klotho. All mice were fed a rescue diet enriched with calcium, phosphorus, and lactose to prevent hyperparathyroidism in VDR mutants, and were killed at 4 weeks of age after double fluorochrome labeling. Kl−/− mice displayed hypercalcemia, hyperphosphatemia, dwarfism, organ atrophy, azotemia, pulmonary emphysema, and osteomalacia. In addition, glucose and insulin tolerance tests revealed hypoglycemia and profoundly increased peripheral insulin sensitivity in Kl−/− mice. Compound mutants were normocalcemic and normophosphatemic, did not show premature aging or organ atrophy, and were phenocopies of VDR mutant mice in terms of body weight, bone mineral density, bone metabolism, serum calcium, serum phosphate, serum PTH, gene expression in parathyroid glands, as well as urinary calcium and phosphate excretion. Furthermore, ablation of vitamin D signaling in double mutants completely normalized glucose and insulin tolerance, indicating that Klotho has no vitamin D independent effects on insulin signaling. Histomorphometry of pancreas islets showed similar beta cell volume per body weight in all groups of animals. In conclusion, our findings cast doubt on a physiologically relevant vitamin D and Fgf23 independent function of Klotho in the regulation of glucose metabolism, bone turnover, and steady-state PTH secretion in vivo

Effects of vitamin D supplementation on endothelial function:a systematic review and meta-analysis of randomised clinical trials

Background: In addition to regulating calcium homoeostasis and bone health, vitamin D influences vascular and metabolic processes including endothelial function (EF) and insulin signalling. This systematic review and meta-analysis of randomised clinical trials (RCTs) were conducted to investigate the effect of vitamin D supplementation on EF and to examine whether the effect size was modified by health status, study duration, dose, route of vitamin D administration, vitamin D status (baseline and post-intervention), body mass index (BMI), age and type of vitamin D.  Methods: We searched the Medline, Embase, Cochrane Library and Scopus databases from inception until March 2015 for studies meeting the following criteria: (1) RCT with adult participants, (2) vitamin D administration alone, (3) studies that quantified EF using commonly applied methods including ultrasound, plethysmography, applanation tonometry and laser Doppler.  Results: Sixteen articles reporting data for 1177 participants were included. Study duration ranged from 4 to 52 weeks. The effect of vitamin D on EF was not significant (SMD: 0.08, 95 % CI −0.06, 0.22, p = 0.28). Subgroup analysis showed a significant improvement of EF in diabetic subjects (SMD: 0.31, 95 % CI 0.05, 0.57, p = 0.02). A non-significant trend was found for diastolic blood pressure (β = 0.02; p = 0.07) and BMI (β = 0.05; p = 0.06).  Conclusions: Vitamin D supplementation did not improve EF. The significant effect of vitamin D in diabetics and a tendency for an association with BMI may indicate a role of excess adiposity and insulin resistance in modulating the effects of vitamin D on vascular function. This remains to be tested in future studies

DIGE Proteome Analysis Reveals Suitability of Ischemic Cardiac In Vitro Model for Studying Cellular Response to Acute Ischemia and Regeneration

Proteomic analysis of myocardial tissue from patient population is suited to yield insights into cellular and molecular mechanisms taking place in cardiovascular diseases. However, it has been limited by small sized biopsies and complicated by high variances between patients. Therefore, there is a high demand for suitable model systems with the capability to simulate ischemic and cardiotoxic effects in vitro, under defined conditions. In this context, we established an in vitro ischemia/reperfusion cardiac disease model based on the contractile HL-1 cell line. To identify pathways involved in the cellular alterations induced by ischemia and thereby defining disease-specific biomarkers and potential target structures for new drug candidates we used fluorescence 2D-difference gel electrophoresis. By comparing spot density changes in ischemic and reperfusion samples we detected several protein spots that were differentially abundant. Using MALDI-TOF/TOF-MS and ESI-MS the proteins were identified and subsequently grouped by functionality. Most prominent were changes in apoptosis signalling, cell structure and energy-metabolism. Alterations were confirmed by analysis of human biopsies from patients with ischemic cardiomyopathy