The klotho gene has been identified as an aging suppressor that encodes a protein involved in cardiovascular disease （CVD）. The inac- tivation of the klotho gene causes serious systemic disorders resembling human ag...The klotho gene has been identified as an aging suppressor that encodes a protein involved in cardiovascular disease （CVD）. The inac- tivation of the klotho gene causes serious systemic disorders resembling human aging, such as atherosderosis, diffuse vascular calcification and shortened life span. Klotho has been demonstrated to ameliorate vascular endothelial dysfunction and delay vascular calcification. Fur- thermore, klotho gene polymorphisms in the human are associated with various cardiovascular events. Recent experiments show that klotho may reduce transient receptor potential canonical6 （TRPC6） channels, resulting in protecting the heart from hypertrophy and systolic dys- function. Fibroblast growth factor23 （FGF23） is a bone-derived hormone that plays an important role in the regulation of phosphate and vi- tamin D metabolism. FGF23 accelerates urinary phosphate excretion and suppresses 1,25-dihydroxy vitaminD3 （1,25（OH）2D3）synthesis in the presence ofFGF receptorl （FGFR1） and its co-receptor ldotho, principally in the kidney. The hormonal affects of circulating klotho pro- tein and FGF23 on vascular and heart have contributed to an understanding of their roles in the pathophysiology of arterial stiffness and left ventricular hypertrophy. Klotho and FGF23 appear to play a critical role in the pathogenesis of vascular disease, and may represent a novel potential therapeutic strategy for clinical intervention.展开更多
Tumor-induced osteomalacia （TIO） is a rare paraneoplastic syndrome in which ectopic production of fibroblast growth factor 23 （FGF23） by non-malignant mesenchymal tumors causes phosphate wasting and bone fractures...Tumor-induced osteomalacia （TIO） is a rare paraneoplastic syndrome in which ectopic production of fibroblast growth factor 23 （FGF23） by non-malignant mesenchymal tumors causes phosphate wasting and bone fractures. Recent studies have implicated the hypoxia-inducible factor-la （HIF-la） in other phosphate wasting disorders caused by elevated FGF23, including X-linked hypophosphatemic rickets and autosomal dominant hypophosphatemia. Here we provide evidence that HIF-la mediates aberrant FGF23 in TIO by transcriptionally activating its promoter. Immunohistochemical studies in phosphaturic mesenchymal tumors resected from patients with documented TIO showed that HIF-la and FGF23 were co-localized in spindle- shaped cells adjacent to blood vessels. Cultured tumor tissue produced high levels of intact FGF23 and demonstrated increased expression of HIF-la protein. Transfection of MC3T3-E1 and Saos-2 cells with a HIF-la expression construct induced the activity of a FGF23 reporter construct. Prior treatment of tumor organ cultures with HIF-la inhibitors decreased HIF-la and FGF23 protein accumulation and inhibited HIF-la-induced luciferase reporter activity in transfected cells. Chromatin immunoprecipitation assays confirmed binding to a HIF-la consensus sequence within the proximal FGF23 promoter, which was eliminated by treatment with a HIF-la inhibitor. These results show for the first time that HIF-la is a direct transcriptional activator of FGF23 and suggest that upregulation of HIF-la activity in TIO contributes to the aberrant FGF23 production in these patients.展开更多
Fibroblast growth factor 23 （FGF23） is a hormone that is mainly secreted by osteocytes and osteoblasts in bone. The critical role of FGF23 in mineral ion homeostasis was first identified in human genetic and acquire...Fibroblast growth factor 23 （FGF23） is a hormone that is mainly secreted by osteocytes and osteoblasts in bone. The critical role of FGF23 in mineral ion homeostasis was first identified in human genetic and acquired rachitic diseases and has been further characterised in animal models. Recent studies have revealed that the levels of FGF23 increase significantly at the very early stages of chronic kidney disease （CKD） and may play a critical role in mineral ion disorders and bone metabolism in these patients. Our recent publications have also shown that FGF23 and its cofactor, Klotho, may play an independent role in directly regulating bone mineralisation instead of producing a systematic effect. In this review, we will discuss the new role of FGF23 in bone mineralisation and the pathophysiology of CKD-related bone disorders.展开更多
多种生物因子参与着慢性肾脏病矿物质和骨代谢异常(chronic kidney disease–mineral and bone disorder,CKD-MBD)的发生发展。除了经典的甲状旁腺激素(PTH)/维生素D轴理论,最近有研究发现成纤维细胞生长因子23(fibroblast growth facto...多种生物因子参与着慢性肾脏病矿物质和骨代谢异常(chronic kidney disease–mineral and bone disorder,CKD-MBD)的发生发展。除了经典的甲状旁腺激素(PTH)/维生素D轴理论,最近有研究发现成纤维细胞生长因子23(fibroblast growth factor23,FGF23)/Klotho、牙基质蛋白1(dentin matrix protein 1,DMP1)、分泌型蛋白Dickkopf-1(secretory protein Dickkopf 1,DKK1)和硬化蛋白(sclerostin)等因子也直接或间接参与着CKD-MBD的进展。本文将对上述因子的最新研究做一综述。展开更多
Background Hypophosphatemic rickets/osteomalacia is a group of diseases characterised by defective mineralization of bone due to hypophosphatemia and low 1,25-dihydroxy vitamin D. To explore the role of fibroblast gro...Background Hypophosphatemic rickets/osteomalacia is a group of diseases characterised by defective mineralization of bone due to hypophosphatemia and low 1,25-dihydroxy vitamin D. To explore the role of fibroblast growth factor 23 （FGF-23） in the regulation of phosphate homeostasis, we measured the circulating concentrations of this growth factor in healthy individuals and in patients with hypophosphatemic rickets/osteomalacia. Methods Nineteen patients with hypophosphatemic rickets/osteomalacia were included in hypophosphatemic group （HP, 12 female and 7 male, mean age was 30 years）, and 19 healthy age-matched individuals served as the control group. Full length FGF-23 fragments were measured by two-site enzyme-linked immunosorbent assay.Results Mean FGF-23 concentrations were significantly higher in the HP group （（87.4±43.6） pg/ml） compared with the control group （（19.2±6.16） pg/ml; P 〈0.001）. In 1 patient with tumour-induced osteomalacia, serum FGF-23 concentrations were 84.1 pg/ml; these concentrations were normalized 2 hours after a hemangiopericytoma resection （7.8 pg/ml）. Subsequently, serum 1,25（OH）2 vitamin D3 concentrations significantly increased from 21.3 pg/ml to 89.3 pg/ml, and serum phosphorus levels were normalized. Conclusions Serum FGF-23 concentrations were markedly elevated in patients with hypophosphatemic rickets. FGF-23 plays an important role in the pathogenesis of hypophosphatemic rickets/osteomalacia.展开更多
Chronic kidney disease （CKD） patients are endangered with the highest mortality rate compared to other chronic diseases. Cardiovascular events account for up to 60% of the fatalities. Cardiovascular calcifcations af...Chronic kidney disease （CKD） patients are endangered with the highest mortality rate compared to other chronic diseases. Cardiovascular events account for up to 60% of the fatalities. Cardiovascular calcifcations affect most of the CKD patients. Most of this calcification is related to disturbed renal phosphate handling. Fibroblast growth factor 23 and klotho defciency were incriminated in the pathogenesis of vascular calcification through different mechanisms including their effects on endothelium and arterial wall smooth muscle cells. In addition, deficient klotho gene expression, a constant feature of CKD, pro-motes vascular pathology and shares in progression of the CKD. The role of gut in the etio-pathogenesis of systemic infammation and vascular calcifcation is a newly discovered mechanism. This review will cover the medical history, prevalence, pathogenesis, clinical relevance, different tools used to diagnose, the ideal timing to prevent or to withhold the progression of vascular cal-cification and the different medications and medical procedures that can help to prolong the survival of CKD patients.展开更多
The kidneys are a vital organ that is vulnerable to both acute kidney injury(AKI)and chronic kidney disease(CKD)which can be caused by numerous risk factors such as ischemia,sepsis,drug toxicity and drug overdose,expo...The kidneys are a vital organ that is vulnerable to both acute kidney injury(AKI)and chronic kidney disease(CKD)which can be caused by numerous risk factors such as ischemia,sepsis,drug toxicity and drug overdose,exposure to heavy metals,and diabetes.In spite of the advances in our understanding of the pathogenesis of AKI and CKD as well AKI transition to CKD,there is still no available therapeutics that can be used to combat kidney disease effectively,highlighting an urgent need to further study the pathological mechanisms underlying AKI,CKD,and AKI progression to CKD.In this regard,animal models of kidney disease are indispensable.This article reviews a widely used animal model of kidney disease,which is induced by folic acid(FA).While a low dose of FA is nutritionally beneficial,a high dose of FA is very toxic to the kidneys.Following a brief description of the procedure for disease induction by FA,major mechanisms of FA-induced kidney injury are then reviewed,including oxidative stress,mitochondrial abnormalities such as impaired bioenergetics and mitophagy,ferroptosis,pyroptosis,and increased expression of fibroblast growth factor 23(FGF23).Finally,application of this FA-induced kidney disease model as a platform for testing the efficacy of a variety of therapeutic approaches is also discussed.Given that this animal model is simple to create and is reproducible,it should remain useful for both studying the pathological mechanisms of kidney disease and identifying therapeutic targets to fight kidney disease.展开更多
The present study was carried out to evaluate the effect of dietary supplemental vitamin D_(3) on fibroblast growth factor 23(FGF23)signals as well as phosphorus homeostasis and metabolism in laying hens.Fourteen 40-w...The present study was carried out to evaluate the effect of dietary supplemental vitamin D_(3) on fibroblast growth factor 23(FGF23)signals as well as phosphorus homeostasis and metabolism in laying hens.Fourteen 40-week-old Hy-Line Brown layers were randomly assigned into 2 treatments:1)vitamin D_(3) restriction group(n=7)fed 0 IU/kg vitamin D_(3) diet,and 2)regular vitamin D_(3) group(n=7)fed 1,600 IU/kg vitamin D_(3) diet.The study lasted for 21 d.Serum parameters,phosphorus and calcium excretion status,and tissue expressions of type II sodium-phosphate co-transporters(NPt2),FGF23 signals and vitamin D_(3) metabolic regulators were determined.Hens fed the vitamin D_(3) restricted diet had decreased serum phosphorus levels(by 31.3%,P=0.028)when compared to those fed regular vitamin D_(3) diet.In response to the decreased serum phosphorus,the vitamin D_(3) restricted laying hens exhibited:1)suppressed kidney expressions of 25-hydroxyvitamin D 1-a-hydroxylase(CYP27B1,by 52.8%,P=0.036)and 1,25-dihydroxyvitamin D 24-hydroxylase(CYP24A1,by 99.4%,P=0.032);2)suppressed serum levels of FGF23(by 14.6%,P=0.048)and increased serum alkaline phosphatase level(by 414.1%,P=0.012);3)decreased calvaria mRNA expressions of fibroblast growth factor receptors(FGFR1,by 85.2%,P=0.003,FGFR2,by 89.4%,P=0.014,FGFR3,by 88.8%,P=0.017,FGFR4,by 89.6%,P=0.030);4)decreased kidney mRNA expressions of FGFR1(by 65.5%,P=0.021),FGFR4(by 66.0%,P=0.050)and KLOTHO(by 68.8%,P=0.038);5)decreased kidney protein expression of type 2a sodium-phosphorus co-transporters(by 54.3%,P=0.039);and 6)increased percent excreta calcium(by 26.9%,P=0.002).In conclusion,the deprivation of dietary vitamin D_(3) decreased FGF23 signals in laying hens by reducing serum FGF23 level and suppressing calvaria and kidney mRNA expressions of FGF23 receptors.展开更多
Erythropoietin(EPO)is the main mediator of erythropoiesis and an important tissue protective hormone that appears to mediate an ancestral neuroprotective innate immune response mechanism at an early age.When the young...Erythropoietin(EPO)is the main mediator of erythropoiesis and an important tissue protective hormone that appears to mediate an ancestral neuroprotective innate immune response mechanism at an early age.When the young brain is threatened-prematurity,neonatal hyperbilirubinemia,malaria-EPO is hypersecreted disproportionately to any concurrent anemic stimuli.Under eons of severe malarial selection pressure,neuroprotective EPO augmenting genetic determinants such as the various hemoglobinopathies,and the angiotensin converting enzyme(ACE)I/D polymorphism,have been positively selected.When malarial and other cerebral threats abate and the young child survives to adulthood,EPO subsides.Sustained high ACE and angiotensin II(Ang II)levels through the ACE D allele in adulthood may then become detrimental as witnessed by epidemiological studies.The ubiquitous renin angiotensin system(RAS)influences theα-klotho/fibroblast growth factor 23(FGF23)circuitry,and both are interconnected with EPO.Here we propose that at a young age,EPO augmenting genetic determinants through ACE D allele elevated Ang II levels in some or HbE/beta thalassemia in others would increase EPO levels and shield against coronavirus disease 2019,akin to protection from malaria and dengue fever.Human evolution may use ACE2 as a“bait”for severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)to gain cellular entry in order to trigger an ACE/ACE2 imbalance and stimulate EPO hypersecretion using tissue RAS,uncoupled from hemoglobin levels.In subjects without EPO augmenting genetic determinants at any age,ACE2 binding and internalization upon SARS-CoV-2 entry would trigger an ACE/ACE2 imbalance,and Ang II oversecretion leading to protective EPO stimulation.In children,low nasal ACE2 Levels would beneficially augment this imbalance,especially for those without protective genetic determinants.On the other hand,in predisposed adults with the ACE D allele,ACE/ACE2 imbalance,may lead to uncontrolled RAS overactivity and an Ang II induced proinflammatory state and immune dysregulation,with interleukin 6(IL-6),plasminogen activator inhibitor,and FGF23 elevations.IL-6 induced EPO suppression,aggravated through co-morbidities such as hypertension,diabetes,obesity,and RAS pharmacological interventions may potentially lead to acute respiratory distress syndrome,cytokine storm and/or autoimmunity.HbE/beta thalassemia carriers would enjoy protection at any age as their EPO stimulation is uncoupled from the RAS system.The timely use of rhEPO,EPO analogs,acetylsalicylic acid,bioactive lipids,or FGF23 antagonists in genetically predisposed individuals may counteract those detrimental effects.展开更多
Fibroblast growth factor 23(FGF23)is a protein synthesized by bone cell and the osteoblast with endocrine function.The main role of FGF23 is to regulate serum phosphorus and 1,25(OH)2 D3 levels,it also plays an import...Fibroblast growth factor 23(FGF23)is a protein synthesized by bone cell and the osteoblast with endocrine function.The main role of FGF23 is to regulate serum phosphorus and 1,25(OH)2 D3 levels,it also plays an important role in calcium and phosphorus metabolism.The role of FGF23 in renal disease is to inhibit of phosphorus reabsorption,promote urinary phosphorus excretion and maintain a stable blood phosphorus level.Patients with chronic kidney disease(CKD)have more risk to suffer cardiovascular disease(CVD)which is related to the abnormal metabolism of calcium and phosphorus.FGF23,as newly discovered cardiovascular risk marker,several studies have shown that FGF23 level associates with multiple cardiovascular risk factors in CKD patients,especially in CKD patients with vascular calcification.To explore its pathogenesis of vascular calcification in CKD patients is particularly important,and that may help to take appropriate measures to improve the prognosis of CKD patients.展开更多
Background:Congenital scoliosis(CS)is a complex spinal malformation of unknown etiology with abnormal bone metabolism.Fibroblast growth factor 23(FGF23),secreted by osteoblasts and osteocytes,can inhibit bone formatio...Background:Congenital scoliosis(CS)is a complex spinal malformation of unknown etiology with abnormal bone metabolism.Fibroblast growth factor 23(FGF23),secreted by osteoblasts and osteocytes,can inhibit bone formation and mineralization.This research aims to investigate the relationship between CS and FGF23.Methods:We collected peripheral blood from two pairs of identical twins for methylation sequencing of the target region.FGF23 mRNA levels in the peripheral blood of CS patients and age-matched controls were measured.Receiver operator characteristic(ROC)curve analyses were conducted to evaluate the specificity and sensitivity of FGF23.The expression levels of FGF23 and its downstream factors fibroblast growth factor receptor 3(FGFr3)/tissue non-specific alkaline phosphatase(TNAP)/osteopontin(OPN)in primary osteoblasts from CS patients(CS-Ob)and controls(CT-Ob)were detected.In addition,the osteogenic abilities of FGF23-knockdown or FGF23-overexpressing Ob were examined.Results:DNA methylation of the FGF23 gene in CS patients was decreased compared to that of their identical twins,accompanied by increased mRNA levels.CS patients had increased peripheral blood FGF23 mRNA levels and decreased computed tomography(CT)values compared with controls.The FGF23 mRNA levels were negatively correlated with the CT value of the spine,and ROCs of FGF23 mRNA levels showed high sensitivity and specificity for CS.Additionally,significantly increased levels of FGF23,FGFr3,OPN,impaired osteogenic mineralization and lower TNAP levels were observed in CS-Ob.Moreover,FGF23 overexpression in CT-Ob increased FGFr3 and OPN levels and decreased TNAP levels,while FGF23 knockdown induced downregulation of FGFr3 and OPN but upregulation of TNAP in CS-Ob.Mineralization of CS-Ob was rescued after FGF23 knockdown.Conclusions:Our results suggested increased peripheral blood FGF23 levels,decreased bone mineral density in CS patients,and a good predictive ability of CS by peripheral blood FGF23 levels.FGF23 may contribute to osteopenia in CS patients through FGFr3/TNAP/OPN pathway.展开更多
Recently,fibroblast growth factor 23(FGF23)has sparked widespread interest because of its potential role in regulating phosphate and vitamin D metabolism.In this review,we summarized the FGF superfamily,the mechanism ...Recently,fibroblast growth factor 23(FGF23)has sparked widespread interest because of its potential role in regulating phosphate and vitamin D metabolism.In this review,we summarized the FGF superfamily,the mechanism of FGF23 on phosphate and vitamin D metabolism,and the FGF23 related bone disease.展开更多
文摘The klotho gene has been identified as an aging suppressor that encodes a protein involved in cardiovascular disease （CVD）. The inac- tivation of the klotho gene causes serious systemic disorders resembling human aging, such as atherosderosis, diffuse vascular calcification and shortened life span. Klotho has been demonstrated to ameliorate vascular endothelial dysfunction and delay vascular calcification. Fur- thermore, klotho gene polymorphisms in the human are associated with various cardiovascular events. Recent experiments show that klotho may reduce transient receptor potential canonical6 （TRPC6） channels, resulting in protecting the heart from hypertrophy and systolic dys- function. Fibroblast growth factor23 （FGF23） is a bone-derived hormone that plays an important role in the regulation of phosphate and vi- tamin D metabolism. FGF23 accelerates urinary phosphate excretion and suppresses 1,25-dihydroxy vitaminD3 （1,25（OH）2D3）synthesis in the presence ofFGF receptorl （FGFR1） and its co-receptor ldotho, principally in the kidney. The hormonal affects of circulating klotho pro- tein and FGF23 on vascular and heart have contributed to an understanding of their roles in the pathophysiology of arterial stiffness and left ventricular hypertrophy. Klotho and FGF23 appear to play a critical role in the pathogenesis of vascular disease, and may represent a novel potential therapeutic strategy for clinical intervention.
基金supported by NIH grants AR049510 (TLC) and AR045955 (LDQ)
文摘Tumor-induced osteomalacia （TIO） is a rare paraneoplastic syndrome in which ectopic production of fibroblast growth factor 23 （FGF23） by non-malignant mesenchymal tumors causes phosphate wasting and bone fractures. Recent studies have implicated the hypoxia-inducible factor-la （HIF-la） in other phosphate wasting disorders caused by elevated FGF23, including X-linked hypophosphatemic rickets and autosomal dominant hypophosphatemia. Here we provide evidence that HIF-la mediates aberrant FGF23 in TIO by transcriptionally activating its promoter. Immunohistochemical studies in phosphaturic mesenchymal tumors resected from patients with documented TIO showed that HIF-la and FGF23 were co-localized in spindle- shaped cells adjacent to blood vessels. Cultured tumor tissue produced high levels of intact FGF23 and demonstrated increased expression of HIF-la protein. Transfection of MC3T3-E1 and Saos-2 cells with a HIF-la expression construct induced the activity of a FGF23 reporter construct. Prior treatment of tumor organ cultures with HIF-la inhibitors decreased HIF-la and FGF23 protein accumulation and inhibited HIF-la-induced luciferase reporter activity in transfected cells. Chromatin immunoprecipitation assays confirmed binding to a HIF-la consensus sequence within the proximal FGF23 promoter, which was eliminated by treatment with a HIF-la inhibitor. These results show for the first time that HIF-la is a direct transcriptional activator of FGF23 and suggest that upregulation of HIF-la activity in TIO contributes to the aberrant FGF23 production in these patients.
基金supported by the National Natural Science Foundation of China (81371173)the Program for New Century Excellent Talents in University (NCET-12-0379)+1 种基金Sichuan Provincial Government Grant (2013JQ0017)supported by Open Fund of State Key Laboratory of Oral Diseases, Sichuan University
文摘Fibroblast growth factor 23 （FGF23） is a hormone that is mainly secreted by osteocytes and osteoblasts in bone. The critical role of FGF23 in mineral ion homeostasis was first identified in human genetic and acquired rachitic diseases and has been further characterised in animal models. Recent studies have revealed that the levels of FGF23 increase significantly at the very early stages of chronic kidney disease （CKD） and may play a critical role in mineral ion disorders and bone metabolism in these patients. Our recent publications have also shown that FGF23 and its cofactor, Klotho, may play an independent role in directly regulating bone mineralisation instead of producing a systematic effect. In this review, we will discuss the new role of FGF23 in bone mineralisation and the pathophysiology of CKD-related bone disorders.
文摘多种生物因子参与着慢性肾脏病矿物质和骨代谢异常(chronic kidney disease–mineral and bone disorder,CKD-MBD)的发生发展。除了经典的甲状旁腺激素(PTH)/维生素D轴理论,最近有研究发现成纤维细胞生长因子23(fibroblast growth factor23,FGF23)/Klotho、牙基质蛋白1(dentin matrix protein 1,DMP1)、分泌型蛋白Dickkopf-1(secretory protein Dickkopf 1,DKK1)和硬化蛋白(sclerostin)等因子也直接或间接参与着CKD-MBD的进展。本文将对上述因子的最新研究做一综述。
基金This study was supported by National Natural Science Foundation of China （NSFC） （No. 30370781） and Doctoral Fund of Ministry of Education of China （No. 20040023055） The authors state that there are no conflicts of interest in this study.
文摘Background Hypophosphatemic rickets/osteomalacia is a group of diseases characterised by defective mineralization of bone due to hypophosphatemia and low 1,25-dihydroxy vitamin D. To explore the role of fibroblast growth factor 23 （FGF-23） in the regulation of phosphate homeostasis, we measured the circulating concentrations of this growth factor in healthy individuals and in patients with hypophosphatemic rickets/osteomalacia. Methods Nineteen patients with hypophosphatemic rickets/osteomalacia were included in hypophosphatemic group （HP, 12 female and 7 male, mean age was 30 years）, and 19 healthy age-matched individuals served as the control group. Full length FGF-23 fragments were measured by two-site enzyme-linked immunosorbent assay.Results Mean FGF-23 concentrations were significantly higher in the HP group （（87.4±43.6） pg/ml） compared with the control group （（19.2±6.16） pg/ml; P 〈0.001）. In 1 patient with tumour-induced osteomalacia, serum FGF-23 concentrations were 84.1 pg/ml; these concentrations were normalized 2 hours after a hemangiopericytoma resection （7.8 pg/ml）. Subsequently, serum 1,25（OH）2 vitamin D3 concentrations significantly increased from 21.3 pg/ml to 89.3 pg/ml, and serum phosphorus levels were normalized. Conclusions Serum FGF-23 concentrations were markedly elevated in patients with hypophosphatemic rickets. FGF-23 plays an important role in the pathogenesis of hypophosphatemic rickets/osteomalacia.
文摘Chronic kidney disease （CKD） patients are endangered with the highest mortality rate compared to other chronic diseases. Cardiovascular events account for up to 60% of the fatalities. Cardiovascular calcifcations affect most of the CKD patients. Most of this calcification is related to disturbed renal phosphate handling. Fibroblast growth factor 23 and klotho defciency were incriminated in the pathogenesis of vascular calcification through different mechanisms including their effects on endothelium and arterial wall smooth muscle cells. In addition, deficient klotho gene expression, a constant feature of CKD, pro-motes vascular pathology and shares in progression of the CKD. The role of gut in the etio-pathogenesis of systemic infammation and vascular calcifcation is a newly discovered mechanism. This review will cover the medical history, prevalence, pathogenesis, clinical relevance, different tools used to diagnose, the ideal timing to prevent or to withhold the progression of vascular cal-cification and the different medications and medical procedures that can help to prolong the survival of CKD patients.
文摘The kidneys are a vital organ that is vulnerable to both acute kidney injury(AKI)and chronic kidney disease(CKD)which can be caused by numerous risk factors such as ischemia,sepsis,drug toxicity and drug overdose,exposure to heavy metals,and diabetes.In spite of the advances in our understanding of the pathogenesis of AKI and CKD as well AKI transition to CKD,there is still no available therapeutics that can be used to combat kidney disease effectively,highlighting an urgent need to further study the pathological mechanisms underlying AKI,CKD,and AKI progression to CKD.In this regard,animal models of kidney disease are indispensable.This article reviews a widely used animal model of kidney disease,which is induced by folic acid(FA).While a low dose of FA is nutritionally beneficial,a high dose of FA is very toxic to the kidneys.Following a brief description of the procedure for disease induction by FA,major mechanisms of FA-induced kidney injury are then reviewed,including oxidative stress,mitochondrial abnormalities such as impaired bioenergetics and mitophagy,ferroptosis,pyroptosis,and increased expression of fibroblast growth factor 23(FGF23).Finally,application of this FA-induced kidney disease model as a platform for testing the efficacy of a variety of therapeutic approaches is also discussed.Given that this animal model is simple to create and is reproducible,it should remain useful for both studying the pathological mechanisms of kidney disease and identifying therapeutic targets to fight kidney disease.
基金the National Natural Science Foundation of China(31902175)Shaanxi Provincial Key Research and Development Program(2019NY-077)+1 种基金Shaanxi Feed Engineering Technology Research Center(2019HBGC-16)the Program for Shaanxi Science&Technology from Shaanxi Provincial Science and Technology Department(2021TD-30).
文摘The present study was carried out to evaluate the effect of dietary supplemental vitamin D_(3) on fibroblast growth factor 23(FGF23)signals as well as phosphorus homeostasis and metabolism in laying hens.Fourteen 40-week-old Hy-Line Brown layers were randomly assigned into 2 treatments:1)vitamin D_(3) restriction group(n=7)fed 0 IU/kg vitamin D_(3) diet,and 2)regular vitamin D_(3) group(n=7)fed 1,600 IU/kg vitamin D_(3) diet.The study lasted for 21 d.Serum parameters,phosphorus and calcium excretion status,and tissue expressions of type II sodium-phosphate co-transporters(NPt2),FGF23 signals and vitamin D_(3) metabolic regulators were determined.Hens fed the vitamin D_(3) restricted diet had decreased serum phosphorus levels(by 31.3%,P=0.028)when compared to those fed regular vitamin D_(3) diet.In response to the decreased serum phosphorus,the vitamin D_(3) restricted laying hens exhibited:1)suppressed kidney expressions of 25-hydroxyvitamin D 1-a-hydroxylase(CYP27B1,by 52.8%,P=0.036)and 1,25-dihydroxyvitamin D 24-hydroxylase(CYP24A1,by 99.4%,P=0.032);2)suppressed serum levels of FGF23(by 14.6%,P=0.048)and increased serum alkaline phosphatase level(by 414.1%,P=0.012);3)decreased calvaria mRNA expressions of fibroblast growth factor receptors(FGFR1,by 85.2%,P=0.003,FGFR2,by 89.4%,P=0.014,FGFR3,by 88.8%,P=0.017,FGFR4,by 89.6%,P=0.030);4)decreased kidney mRNA expressions of FGFR1(by 65.5%,P=0.021),FGFR4(by 66.0%,P=0.050)and KLOTHO(by 68.8%,P=0.038);5)decreased kidney protein expression of type 2a sodium-phosphorus co-transporters(by 54.3%,P=0.039);and 6)increased percent excreta calcium(by 26.9%,P=0.002).In conclusion,the deprivation of dietary vitamin D_(3) decreased FGF23 signals in laying hens by reducing serum FGF23 level and suppressing calvaria and kidney mRNA expressions of FGF23 receptors.
文摘Erythropoietin(EPO)is the main mediator of erythropoiesis and an important tissue protective hormone that appears to mediate an ancestral neuroprotective innate immune response mechanism at an early age.When the young brain is threatened-prematurity,neonatal hyperbilirubinemia,malaria-EPO is hypersecreted disproportionately to any concurrent anemic stimuli.Under eons of severe malarial selection pressure,neuroprotective EPO augmenting genetic determinants such as the various hemoglobinopathies,and the angiotensin converting enzyme(ACE)I/D polymorphism,have been positively selected.When malarial and other cerebral threats abate and the young child survives to adulthood,EPO subsides.Sustained high ACE and angiotensin II(Ang II)levels through the ACE D allele in adulthood may then become detrimental as witnessed by epidemiological studies.The ubiquitous renin angiotensin system(RAS)influences theα-klotho/fibroblast growth factor 23(FGF23)circuitry,and both are interconnected with EPO.Here we propose that at a young age,EPO augmenting genetic determinants through ACE D allele elevated Ang II levels in some or HbE/beta thalassemia in others would increase EPO levels and shield against coronavirus disease 2019,akin to protection from malaria and dengue fever.Human evolution may use ACE2 as a“bait”for severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)to gain cellular entry in order to trigger an ACE/ACE2 imbalance and stimulate EPO hypersecretion using tissue RAS,uncoupled from hemoglobin levels.In subjects without EPO augmenting genetic determinants at any age,ACE2 binding and internalization upon SARS-CoV-2 entry would trigger an ACE/ACE2 imbalance,and Ang II oversecretion leading to protective EPO stimulation.In children,low nasal ACE2 Levels would beneficially augment this imbalance,especially for those without protective genetic determinants.On the other hand,in predisposed adults with the ACE D allele,ACE/ACE2 imbalance,may lead to uncontrolled RAS overactivity and an Ang II induced proinflammatory state and immune dysregulation,with interleukin 6(IL-6),plasminogen activator inhibitor,and FGF23 elevations.IL-6 induced EPO suppression,aggravated through co-morbidities such as hypertension,diabetes,obesity,and RAS pharmacological interventions may potentially lead to acute respiratory distress syndrome,cytokine storm and/or autoimmunity.HbE/beta thalassemia carriers would enjoy protection at any age as their EPO stimulation is uncoupled from the RAS system.The timely use of rhEPO,EPO analogs,acetylsalicylic acid,bioactive lipids,or FGF23 antagonists in genetically predisposed individuals may counteract those detrimental effects.
基金Construction of collaborative platform for clin ical re search and clinical research of blood purification(201604020175)Guang dong University blood purification tech nology and Engineering Research Center(GCZX-A1104)+2 种基金Guangdong Obers Blood Purification A ca demi cian Work station(2013B090400004)Guangdong Provincial Center for clinical en gineering of blood purification(507204531040)Guangzhou entrepreneurial leader talent/LCY201215
文摘Fibroblast growth factor 23(FGF23)is a protein synthesized by bone cell and the osteoblast with endocrine function.The main role of FGF23 is to regulate serum phosphorus and 1,25(OH)2 D3 levels,it also plays an important role in calcium and phosphorus metabolism.The role of FGF23 in renal disease is to inhibit of phosphorus reabsorption,promote urinary phosphorus excretion and maintain a stable blood phosphorus level.Patients with chronic kidney disease(CKD)have more risk to suffer cardiovascular disease(CVD)which is related to the abnormal metabolism of calcium and phosphorus.FGF23,as newly discovered cardiovascular risk marker,several studies have shown that FGF23 level associates with multiple cardiovascular risk factors in CKD patients,especially in CKD patients with vascular calcification.To explore its pathogenesis of vascular calcification in CKD patients is particularly important,and that may help to take appropriate measures to improve the prognosis of CKD patients.
基金National Natural Science Foundation of China(No.82072390)Natural Science Foundation of Hunan,China(No.2020JJ4873)
文摘Background:Congenital scoliosis(CS)is a complex spinal malformation of unknown etiology with abnormal bone metabolism.Fibroblast growth factor 23(FGF23),secreted by osteoblasts and osteocytes,can inhibit bone formation and mineralization.This research aims to investigate the relationship between CS and FGF23.Methods:We collected peripheral blood from two pairs of identical twins for methylation sequencing of the target region.FGF23 mRNA levels in the peripheral blood of CS patients and age-matched controls were measured.Receiver operator characteristic(ROC)curve analyses were conducted to evaluate the specificity and sensitivity of FGF23.The expression levels of FGF23 and its downstream factors fibroblast growth factor receptor 3(FGFr3)/tissue non-specific alkaline phosphatase(TNAP)/osteopontin(OPN)in primary osteoblasts from CS patients(CS-Ob)and controls(CT-Ob)were detected.In addition,the osteogenic abilities of FGF23-knockdown or FGF23-overexpressing Ob were examined.Results:DNA methylation of the FGF23 gene in CS patients was decreased compared to that of their identical twins,accompanied by increased mRNA levels.CS patients had increased peripheral blood FGF23 mRNA levels and decreased computed tomography(CT)values compared with controls.The FGF23 mRNA levels were negatively correlated with the CT value of the spine,and ROCs of FGF23 mRNA levels showed high sensitivity and specificity for CS.Additionally,significantly increased levels of FGF23,FGFr3,OPN,impaired osteogenic mineralization and lower TNAP levels were observed in CS-Ob.Moreover,FGF23 overexpression in CT-Ob increased FGFr3 and OPN levels and decreased TNAP levels,while FGF23 knockdown induced downregulation of FGFr3 and OPN but upregulation of TNAP in CS-Ob.Mineralization of CS-Ob was rescued after FGF23 knockdown.Conclusions:Our results suggested increased peripheral blood FGF23 levels,decreased bone mineral density in CS patients,and a good predictive ability of CS by peripheral blood FGF23 levels.FGF23 may contribute to osteopenia in CS patients through FGFr3/TNAP/OPN pathway.
文摘Recently,fibroblast growth factor 23(FGF23)has sparked widespread interest because of its potential role in regulating phosphate and vitamin D metabolism.In this review,we summarized the FGF superfamily,the mechanism of FGF23 on phosphate and vitamin D metabolism,and the FGF23 related bone disease.
