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da Silva MMR, Bilezikian JP, de Paula FJA. Phosphate metabolism: its impact on disorders of mineral metabolism. Endocrine 2025; 88:1-13. [PMID: 39527339 DOI: 10.1007/s12020-024-04092-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 10/29/2024] [Indexed: 11/16/2024]
Abstract
Regulatory molecules typically work cooperatively to ensure the efficient functioning of hormonal systems. Examples include LH and FSH in reproductive biology, insulin and glucagon in glucose metabolism. Similarly, calcium and phosphorus are important regulators of skeletal homeostasis. In the circulation, these molecules are under the control of PTH, 1,25(OHD), and FGF23. In turn, these hormones depend upon a mutual and complex interplay among themselves. For example, alterations in calcium metabolism influence phosphorus homeostasis, as occurs in primary hyperparathyroidism (PHPT). Not as well recognized is the influence that abnormalities in phosphorus metabolism can have on calcium homeostasis. In this review, we call attention to the impact that abnormalities in phosphorus can have on calcium metabolism.
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Affiliation(s)
- Maisa Monseff Rodrigues da Silva
- Department of Internal Medicine, Ribeirao Preto Medical School, University of São Paulo, 3900 Bandeirantes Ave, Ribeirão Preto, SP, Brazil
| | - John P Bilezikian
- Department of Medicine, Division of Endocrinology, Vagelos College of Physicians and Surgeons. Columbia University, New York, NY, USA
| | - Francisco J A de Paula
- Department of Internal Medicine, Ribeirao Preto Medical School, University of São Paulo, 3900 Bandeirantes Ave, Ribeirão Preto, SP, Brazil.
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Mizukami Y, Kawao N, Ohira T, Okada K, Yamao H, Matsuo O, Kaji H. Effects of plasminogen activator inhibitor-1 deficiency on bone disorders and sarcopenia caused by adenine-induced renal dysfunction in mice. PLoS One 2024; 19:e0311902. [PMID: 39388484 PMCID: PMC11469609 DOI: 10.1371/journal.pone.0311902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Accepted: 09/27/2024] [Indexed: 10/12/2024] Open
Abstract
Chronic kidney disease (CKD) is a significant global health issue and often involves CKD-mineral and bone disorder (MBD) and sarcopenia. Plasminogen activator inhibitor-1 (PAI-1) is an inhibitor of fibrinolysis. PAI-1 has been implicated in the pathogenesis of osteoporosis and muscle wasting induced by inflammatory conditions. However, the roles of PAI-1 in CKD-MBD and sarcopenia remain unknown. Therefore, the present study investigated the roles of PAI-1 in bone loss and muscle wasting induced by adenine in PAI-1-deficient mice. CKD was induced in PAI-1+/+ and PAI-1-/- mice by administration of adenine for ten weeks. Muscle wasting was assessed by grip strength test, quantitative computed tomography (CT) analysis and muscle weight measurement. Osteoporosis was assessed by micro-CT analysis of femoral microstructural parameters. PAI-1 deficiency did not affect adenine-induced decreases in body weight and food intake or renal dysfunction in male or female mice. PAI-1 deficiency also did not affect adenine-induced decreases in grip strength, muscle mass in the lower limbs, or the tissue weights of the gastrocnemius, soleus, and tibialis anterior muscles in male or female mice. PAI-1 deficiency aggravated trabecular bone loss in CKD-induced male mice, but significantly increased trabecular bone in CKD-induced female mice. On the other hand, PAI-1 deficiency did not affect cortical bone loss in CKD-induced mice. In conclusion, PAI-1 is not critical for the pathophysiology of CKD-MBD or CKD-induced sarcopenia in mice. However, PAI-1 may be partly related to bone metabolism in trabecular bone in the CKD state with sex differences.
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Affiliation(s)
- Yuya Mizukami
- Kindai University Faculty of Medicine, Department of Physiology and Regenerative Medicine, Osakasayama, Osaka, Japan
| | - Naoyuki Kawao
- Kindai University Faculty of Medicine, Department of Physiology and Regenerative Medicine, Osakasayama, Osaka, Japan
| | - Takashi Ohira
- Kindai University Faculty of Medicine, Department of Physiology and Regenerative Medicine, Osakasayama, Osaka, Japan
| | - Kiyotaka Okada
- Kindai University Faculty of Medicine, Department of Physiology and Regenerative Medicine, Osakasayama, Osaka, Japan
| | - Hisatoshi Yamao
- Kindai University Faculty of Medicine, Department of Physiology and Regenerative Medicine, Osakasayama, Osaka, Japan
| | - Osamu Matsuo
- Kindai University Faculty of Medicine, Department of Physiology and Regenerative Medicine, Osakasayama, Osaka, Japan
| | - Hiroshi Kaji
- Kindai University Faculty of Medicine, Department of Physiology and Regenerative Medicine, Osakasayama, Osaka, Japan
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Qin Y, Teng Y, Yang Y, Mao Z, Zhao S, Zhang N, Li X, Niu W. Advancements in inhibitors of crucial enzymes in the cysteine biosynthetic pathway: Serine acetyltransferase and O-acetylserine sulfhydrylase. Chem Biol Drug Des 2024; 104:e14573. [PMID: 38965664 DOI: 10.1111/cbdd.14573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 05/17/2024] [Accepted: 06/18/2024] [Indexed: 07/06/2024]
Abstract
Infectious diseases have been jeopardized problem that threaten public health over a long period of time. The growing prevalence of drug-resistant pathogens and infectious cases have led to a decrease in the number of effective antibiotics, which highlights the urgent need for the development of new antibacterial agents. Serine acetyltransferase (SAT), also known as CysE in certain bacterial species, and O-acetylserine sulfhydrylase (OASS), also known as CysK in select bacteria, are indispensable enzymes within the cysteine biosynthesis pathway of various pathogenic microorganisms. These enzymes play a crucial role in the survival of these pathogens, making SAT and OASS promising targets for the development of novel anti-infective agents. In this comprehensive review, we present an introduction to the structure and function of SAT and OASS, along with an overview of existing inhibitors for SAT and OASS as potential antibacterial agents. Our primary focus is on elucidating the inhibitory activities, structure-activity relationships, and mechanisms of action of these inhibitors. Through this exploration, we aim to provide insights into promising strategies and prospects in the development of antibacterial agents that target these essential enzymes.
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Affiliation(s)
- Yinhui Qin
- Department of Pharmacy, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, Henan, China
| | - Yuetai Teng
- Department of Pharmacy, Jinan Vocational College of Nursing, Jinan, China
| | - Yan Yang
- Department of Pharmacy, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, Henan, China
| | - Zhenkun Mao
- Department of Pharmacy, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, Henan, China
| | - Shengyu Zhao
- Shenyang Pharmaceutical University, Shenyang, China
| | - Na Zhang
- Shandong Academy of Chinese Medicine, Jinan, China
| | - Xu Li
- Institute of Chemistry Henan Academy of Sciences, Zhengzhou, Henan, China
| | - Weihong Niu
- Department of Pathology, Henan Key Laboratory for Digital Pathology Medicine, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, Henan, China
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Qian C, Ito N, Tsuji K, Sato S, Kikuchi K, Yoshii T, Miyata T, Asou Y. A PAI-1 antagonist ameliorates hypophosphatemia in the Hyp vitamin D-resistant rickets model mouse. FEBS Open Bio 2024; 14:290-299. [PMID: 38050660 PMCID: PMC10839342 DOI: 10.1002/2211-5463.13745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 11/20/2023] [Accepted: 12/04/2023] [Indexed: 12/06/2023] Open
Abstract
Congenital fibroblast growth factor 23 (FGF23)-related hypophosphatemic rickets/osteomalacia is a rare bone metabolism disorder characterized by hypophosphatemia and caused by genetic abnormalities that result in excessive secretion of FGF23. Hyp mice are a model of X-linked hypophosphatemia (XLH) caused by deletion of the PHEX gene and excessive production of FGF23. The purpose of this study was to investigate the potential of TM5614 as a therapeutic agent for the treatment of congenital FGF23-related hypophosphatemic rickets and osteomalacia in humans by administering TM5614 to Hyp mice and examining its curative effect on hypophosphatemia. After a single oral administration of TM5614 10 mg·kg-1 to female Hyp mice starting at 17 weeks of age, the serum phosphate concentration increased with a peak at 6 h after administration. ELISA confirmed that TM5614 administration decreased the intact FGF23 concentration in the blood. Expression of 25-hydroxyvitamin D-1α-hydroxylase protein encoded by Cyp27b1 mRNA in the kidney was suppressed in Hyp mice, and treatment with 10 mg·kg-1 of TM5614 normalized the expression of 25-hydroxyvitamin D-1α-hydroxylase protein and Cyp27b1 mRNA in the kidneys of these mice. Our data indicate that oral administration of TM5614 ameliorates hypophosphatemia in Hyp mice, suggesting that TM5614 may be an effective treatment for congenital FGF23-related hypophosphatemic rickets and osteomalacia.
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Affiliation(s)
- Cheng Qian
- Department of Orthopedics SurgeryTokyo Medical and Dental UniversityJapan
| | - Nobuaki Ito
- Division of Nephrology and EndocrinologyThe University of Tokyo HospitalJapan
| | - Kunikazu Tsuji
- Department of Orthopedics SurgeryTokyo Medical and Dental UniversityJapan
| | - Shingo Sato
- Department of Orthopedics SurgeryTokyo Medical and Dental UniversityJapan
| | - Katsushi Kikuchi
- Department of Orthopedics SurgeryTokyo Medical and Dental UniversityJapan
| | - Toshitaka Yoshii
- Department of Orthopedics SurgeryTokyo Medical and Dental UniversityJapan
| | - Toshio Miyata
- United Centers for Advanced Research and Translational MedicineTohoku UniversitySendaiJapan
| | - Yoshinori Asou
- Department of Orthopedics SurgeryTokyo Medical and Dental UniversityJapan
- China‐Japan Friendship Institution of MedicineShanghai UniversityChina
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Rodriguez G, Eren M, Haupfear I, Viola KL, Cline EN, Miyata T, Klein WL, Vaughan DE, Dong H. Pharmacological inhibition of plasminogen activator inhibitor-1 prevents memory deficits and reduces neuropathology in APP/PS1 mice. Psychopharmacology (Berl) 2023; 240:2641-2655. [PMID: 37700086 DOI: 10.1007/s00213-023-06459-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 08/28/2023] [Indexed: 09/14/2023]
Abstract
RATIONALE Extracellular proteolytic activity plays an important role in memory formation and the preservation of cognitive function. Previous studies have shown increased levels of plasminogen activator inhibitor-1 (PAI-1) in the brain of mouse models of Alzheimer's disease (AD) and plasma of AD patients, associated with memory and cognitive decline; however, the exact function of PAI-1 in AD onset and progression is largely unclear. OBJECTIVE In this study, we evaluated a novel PAI-1 inhibitor, TM5A15, on its ability to prevent or reverse memory deficits and decrease Aβ levels and plaque deposition in APP/PS1 mice. METHODS We administered TM5A15 mixed in a chow diet to 3-month and 9-month-old APP/PS1 mice before and after neuropathological changes were distinguishable. We then evaluated the effects of TM5A15 on memory function and neuropathology at 9 months and 18 months of age. RESULTS In the younger mice, 6 months of TM5A15 treatment protected against recognition and short-term working memory impairment. TM5A15 also decreased oligomer levels and amyloid plaques, and increased mBDNF expression in APP/PS1 mice at 9 months of age. In aged mice, 9 months of TM5A15 treatment did not significantly improve memory function nor decrease amyloid plaques. However, TM5A15 treatment showed a trend in decreasing oligomer levels in APP/PS1 mice at 18 months of age. CONCLUSION Our results suggest that PAI-1 inhibition could improve memory function and reduce the accumulation of amyloid levels in APP/PS1 mice. Such effects are more prominent when TM5A15 is administered before advanced AD pathology and memory deficits occur.
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Affiliation(s)
- Guadalupe Rodriguez
- Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, Ward 7-103, Chicago, IL, 60611, USA
| | - Mesut Eren
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
| | - Isabel Haupfear
- Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, Ward 7-103, Chicago, IL, 60611, USA
| | - Kirsten L Viola
- Department of Neurobiology, Northwestern University, 2205 Tech Drive, Hogan 4-160, Evanston, IL, 60208, USA
| | - Erika N Cline
- Department of Neurobiology, Northwestern University, 2205 Tech Drive, Hogan 4-160, Evanston, IL, 60208, USA
| | - Toshio Miyata
- Department of Molecular Medicine and Therapy, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - William L Klein
- Department of Neurobiology, Northwestern University, 2205 Tech Drive, Hogan 4-160, Evanston, IL, 60208, USA
| | - Douglas E Vaughan
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
| | - Hongxin Dong
- Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, Ward 7-103, Chicago, IL, 60611, USA.
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Aobulikasimu A, Liu T, Piao J, Sato S, Ochi H, Okawa A, Tsuji K, Asou Y. SIRT6-PAI-1 axis is a promising therapeutic target in aging-related bone metabolic disruption. Sci Rep 2023; 13:7991. [PMID: 37198221 DOI: 10.1038/s41598-023-33297-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 04/11/2023] [Indexed: 05/19/2023] Open
Abstract
The mechanistic regulation of bone mass in aged animals is poorly understood. In this study, we examined the role of SIRT6, a longevity-associated factor, in osteocytes, using mice lacking Sirt6 in Dmp-1-expressing cells (cKO mice) and the MLO-Y4 osteocyte-like cell line. cKO mice exhibited increased osteocytic expression of Sost, Fgf23 and senescence inducing gene Pai-1 and the senescence markers p16 and Il-6, decreased serum phosphate levels, and low-turnover osteopenia. The cKO phenotype was reversed in mice that were a cross of PAI-1-null mice with cKO mice. Furthermore, senescence induction in MLO-Y4 cells increased the Fgf23 and Sost mRNA expression. Sirt6 knockout and senescence induction increased HIF-1α binding to the Fgf23 enhancer sequence. Bone mass and serum phosphate levels were higher in PAI-1-null aged mice than in wild-type mice. Therefore, SIRT6 agonists or PAI-1 inhibitors may be promising therapeutic options for aging-related bone metabolism disruptions.
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Affiliation(s)
- Alkebaier Aobulikasimu
- Department of Orthopedics Surgery, Tokyo Medical and Dental University, 1-5-45 Yushima Bunkyo-Ku, Tokyo, 113-8519, Japan
| | - Tao Liu
- Department of Orthopedics Surgery, Tokyo Medical and Dental University, 1-5-45 Yushima Bunkyo-Ku, Tokyo, 113-8519, Japan
| | - Jinying Piao
- Department of Orthopedics Surgery, Tokyo Medical and Dental University, 1-5-45 Yushima Bunkyo-Ku, Tokyo, 113-8519, Japan
| | - Shingo Sato
- Department of Orthopedics Surgery, Tokyo Medical and Dental University, 1-5-45 Yushima Bunkyo-Ku, Tokyo, 113-8519, Japan
| | - Hiroki Ochi
- Department of Rehabilitation for Movement Functions, Research Institute, National Rehabilitation Center for Persons With Disabilities, Tokorozawa-Shi, Saitama, Japan
| | - Atsushi Okawa
- Department of Orthopedics Surgery, Tokyo Medical and Dental University, 1-5-45 Yushima Bunkyo-Ku, Tokyo, 113-8519, Japan
| | - Kunikazu Tsuji
- Department of Orthopedics Surgery, Tokyo Medical and Dental University, 1-5-45 Yushima Bunkyo-Ku, Tokyo, 113-8519, Japan
| | - Yoshinori Asou
- Department of Orthopedics Surgery, Tokyo Medical and Dental University, 1-5-45 Yushima Bunkyo-Ku, Tokyo, 113-8519, Japan.
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Jiang CS, Rana T, Jin LW, Farr SA, Morley JE, Qin H, Liu G, Liu RM. Aging, Plasminogen Activator Inhibitor 1, Brain Cell Senescence, and Alzheimer's Disease. Aging Dis 2023; 14:515-528. [PMID: 37008063 PMCID: PMC10017160 DOI: 10.14336/ad.2022.1220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 12/20/2022] [Indexed: 04/04/2023] Open
Abstract
The etiology for late-onset Alzheimer's disease (LOAD), which accounts for >95% of Alzheimer's disease (AD) cases, is unknown. Emerging evidence suggests that cellular senescence contributes importantly to AD pathophysiology, although the mechanisms underlying brain cell senescence and by which senescent cells promote neuro-pathophysiology remain unclear. In this study we show for the first time that the expression of plasminogen activator inhibitor 1 (PAI-1), a serine protease inhibitor, is increased, in correlation with the increased expression of cell cycle repressors p53 and p21, in the hippocampus/cortex of senescence accelerated mouse prone 8 (SAMP8) mice and LOAD patients. Double immunostaining results show that astrocytes in the brain of LOAD patients and SAMP8 mice express higher levels of senescent markers and PAI-1, compared to astrocytes in the corresponding controls. In vitro studies further show that overexpression of PAI-1 alone, intracellularly or extracellularly, induced senescence, whereas inhibition or silencing PAI-1 attenuated H2O2-induced senescence, in primary mouse and human astrocytes. Treatment with the conditional medium (CM) from senescent astrocytes induced neuron apoptosis. Importantly, the PAI-1 deficient CM from senescent astrocytes that overexpress a secretion deficient PAI-1 (sdPAI-1) has significantly reduced effect on neurons, compared to the PAI-1 containing CM from senescent astrocytes overexpressing wild type PAI-1 (wtPAI-1), although sdPAI-1 and wtPAI-1 induce similar degree of astrocyte senescence. Together, our results suggest that increased PAI-1, intracellularly or extracellularly, may contribute to brain cell senescence in LOAD and that senescent astrocytes can induce neuron apoptosis through secreting pathologically active molecules, including PAI-1.
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Affiliation(s)
- Chun-Sun Jiang
- Department of Medicine, University of Alabama at Birmingham (UAB), Birmingham, AL, USA.
| | - Tapasi Rana
- Department of Medicine, University of Alabama at Birmingham (UAB), Birmingham, AL, USA.
| | - Lee-Way Jin
- Department of Pathology and Laboratory Medicine, University of California, Davis, CA, USA.
| | - Susan A Farr
- Division of Geriatric Medicine, School of Medicine, Saint Louis University, St. Louis, MO, USA.
- Research and Development, Veterans Affairs Medical Center, St. Louis Missouri, MO, USA.
| | - John E Morley
- Division of Geriatric Medicine, School of Medicine, Saint Louis University, St. Louis, MO, USA.
| | - Hongwei Qin
- Department of Cell, Developmental and Integrative Biology, UAB, Birmingham, AL, USA.
| | - Gang Liu
- Department of Medicine, University of Alabama at Birmingham (UAB), Birmingham, AL, USA.
| | - Rui-Ming Liu
- Department of Medicine, University of Alabama at Birmingham (UAB), Birmingham, AL, USA.
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Portales-Castillo I, Simic P. PTH, FGF-23, Klotho and Vitamin D as regulators of calcium and phosphorus: Genetics, epigenetics and beyond. Front Endocrinol (Lausanne) 2022; 13:992666. [PMID: 36246903 PMCID: PMC9558279 DOI: 10.3389/fendo.2022.992666] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 09/12/2022] [Indexed: 11/30/2022] Open
Abstract
The actions of several bone-mineral ion regulators, namely PTH, FGF23, Klotho and 1,25(OH)2 vitamin D (1,25(OH)2D), control calcium and phosphate metabolism, and each of these molecules has additional biological effects related to cell signaling, metabolism and ultimately survival. Therefore, these factors are tightly regulated at various levels - genetic, epigenetic, protein secretion and cleavage. We review the main determinants of mineral homeostasis including well-established genetic and post-translational regulators and bring attention to the epigenetic mechanisms that affect the function of PTH, FGF23/Klotho and 1,25(OH)2D. Clinically relevant epigenetic mechanisms include methylation of cytosine at CpG-rich islands, histone deacetylation and micro-RNA interference. For example, sporadic pseudohypoparathyroidism type 1B (PHP1B), a disease characterized by resistance to PTH actions due to blunted intracellular cAMP signaling at the PTH/PTHrP receptor, is associated with abnormal methylation at the GNAS locus, thereby leading to reduced expression of the stimulatory G protein α-subunit (Gsα). Post-translational regulation is critical for the function of FGF-23 and such modifications include glycosylation and phosphorylation, which regulate the cleavage of FGF-23 and hence the proportion of available FGF-23 that is biologically active. While there is extensive data on how 1,25(OH)2D and the vitamin D receptor (VDR) regulate other genes, much more needs to be learned about their regulation. Reduced VDR expression or VDR mutations are the cause of rickets and are thought to contribute to different disorders. Epigenetic changes, such as increased methylation of the VDR resulting in decreased expression are associated with several cancers and infections. Genetic and epigenetic determinants play crucial roles in the function of mineral factors and their disorders lead to different diseases related to bone and beyond.
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Affiliation(s)
- Ignacio Portales-Castillo
- Department of Medicine, Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
- Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Petra Simic
- Department of Medicine, Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
- Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
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Luther JM, Fogo AB. The role of mineralocorticoid receptor activation in kidney inflammation and fibrosis. Kidney Int Suppl (2011) 2022; 12:63-68. [DOI: 10.1016/j.kisu.2021.11.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/15/2021] [Accepted: 11/08/2021] [Indexed: 12/20/2022] Open
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Xu J, Xu Y. Identifying of miRNA–mRNA Regulatory Networks Associated with Acute Kidney Injury by Weighted Gene Co-Expression Network Analysis. Int J Gen Med 2022; 15:1853-1864. [PMID: 35221717 PMCID: PMC8865863 DOI: 10.2147/ijgm.s353484] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 02/10/2022] [Indexed: 01/07/2023] Open
Abstract
Background Acute kidney injury (AKI) is a clinical emergency characterized by a dramatic decline in renal function and the accumulation of metabolic waste products in the body, with a high morbidity and mortality rate. The pathogenesis of AKI remains unclear and there are no effective treatment options. Methods We aimed to identify critical genes involved in the pathogenesis of AKI and construct a miRNA–mRNA regulatory network using gene expression data downloaded from Gene Expression Omnibus (GSE85957) for 38 kidneys of AKI and 19 control rats and cisplatin treated kidneys of 3 AKI and 3 control rats. Data in GSE85957 were processed using weighted gene co-expression network analysis (WGCNA), and biological function analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were used to analyze the functions associated with critical genes. Results Twenty-eight modules in the GSE85957 dataset were identified by WGCNA, of which 103 genes in the orange module and 30 genes in the black module were closely associated with AKI and dose. Biological function analysis of genes in the orange and black modules revealed that skeletal muscle cell differentiation, tissue development and organ development were involved in the pathological changes of AKI. Combining with our experimentally processed AKI rat kidney data, eight genes (Atf3, Egr1, Egr2, Fos, Fosb, Gdf15, Serpine1 and Nr1d1) were identified as potential biomarkers of AKI, and miRNA–mRNA regulatory networks were constructed based on the above eight critical genes. Further tissue validation revealed that Egr1 and Fos were highly expressed in AKI. Conclusion Our study identified potential biomarkers of AKI and constructed an associated miRNA–mRNA regulatory network, which may provide new insights into the molecular pathogenesis of AKI.
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Affiliation(s)
- Jie Xu
- Department of Urology, Pudong New Area People’s Hospital, Shanghai, 201299, People’s Republic of China
- Correspondence: Jie Xu, Department of Urology, Pudong New Area People’s Hospital, No. 490, Chuanhuan South Road, Pudong New Area, Shanghai, 201299, People’s Republic of China, Tel/Fax +86-13816833210, Email
| | - Yunfei Xu
- Department of Urology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200072, People’s Republic of China
- Yunfei Xu, Department of Urology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, No. 301, Yanchang Road, Jing’an District, Shanghai, 200072, People’s Republic of China, Email
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11
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The regulation of FGF23 under physiological and pathophysiological conditions. Pflugers Arch 2022; 474:281-292. [PMID: 35084563 PMCID: PMC8837506 DOI: 10.1007/s00424-022-02668-w] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/18/2022] [Accepted: 01/19/2022] [Indexed: 12/18/2022]
Abstract
Fibroblast growth factor 23 (FGF23) is an important bone hormone that regulates phosphate homeostasis in the kidney along with active vitamin D (1,25(OH)2D3) and parathyroid hormone (PTH). Endocrine effects of FGF23 depend, at least in part, on αKlotho functioning as a co-receptor whereas further paracrine effects in other tissues are αKlotho-independent. Regulation of FGF23 production is complex under both, physiological and pathophysiological conditions. Physiological regulators of FGF23 include, but are not limited to, 1,25(OH)2D3, PTH, dietary phosphorus intake, and further intracellular and extracellular factors, kinases, cytokines, and hormones. Moreover, several acute and chronic diseases including chronic kidney disease (CKD) or further cardiovascular disorders are characterized by early rises in the plasma FGF23 level pointing to further mechanisms effective in the regulation of FGF23 under pathophysiological conditions. Therefore, FGF23 also serves as a prognostic marker in several diseases. Our review aims to comprehensively summarize the regulation of FGF23 in health and disease.
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12
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Papadopoulos KI, Sutheesophon W, Manipalviratn S, Aw TC. Age and genotype dependent erythropoietin protection in COVID-19. World J Stem Cells 2021; 13:1513-1529. [PMID: 34786155 PMCID: PMC8567454 DOI: 10.4252/wjsc.v13.i10.1513] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 06/23/2021] [Accepted: 09/19/2021] [Indexed: 02/06/2023] Open
Abstract
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 hyper-secreted 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 the α-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.
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Affiliation(s)
| | | | - Somjate Manipalviratn
- Department of Reproductive Endocrinology, Jetanin Institute for Assisted Reproduction, Bangkok 10330, Thailand
| | - Tar-Choon Aw
- Department of Laboratory Medicine, Changi General Hospital, Singapore 529889, Singapore
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13
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Hu PP, Bao JF, Li A. Roles for fibroblast growth factor-23 and α-Klotho in acute kidney injury. Metabolism 2021; 116:154435. [PMID: 33220250 DOI: 10.1016/j.metabol.2020.154435] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 11/08/2020] [Accepted: 11/13/2020] [Indexed: 12/21/2022]
Abstract
Acute kidney injury is a global disease with high morbidity and mortality. Recent studies have revealed that the fibroblast growth factor-23-α-Klotho axis is closely related to chronic kidney disease, and has multiple biological functions beyond bone-mineral metabolism. However, although dysregulation of fibroblast growth factor-23-α-Klotho has been observed in acute kidney injury, the role of fibroblast growth factor-23-α-Klotho in the pathophysiology of acute kidney injury remains largely unknown. In this review, we describe recent findings regarding fibroblast growth factor-23-α-Klotho, which is mainly involved in inflammation, oxidative stress, and hemodynamic disorders. Further, based on these recent results, we put forth novel insights regarding the relationship between the fibroblast growth factor-23-α-Klotho axis and acute kidney injury, which may provide new therapeutic targets for treating acute kidney injury.
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Affiliation(s)
- Pan-Pan Hu
- State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, 510005 Guangzhou, China
| | - Jing-Fu Bao
- State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, 510005 Guangzhou, China
| | - Aiqing Li
- State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, 510005 Guangzhou, China.
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14
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Yahata T, Ibrahim AA, Hirano KI, Muguruma Y, Naka K, Hozumi K, Vaughan DE, Miyata T, Ando K. Targeting of plasminogen activator inhibitor-1 activity promotes elimination of chronic myeloid leukemia stem cells. Haematologica 2021; 106:483-494. [PMID: 32001531 PMCID: PMC7849585 DOI: 10.3324/haematol.2019.230227] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2019] [Accepted: 01/24/2020] [Indexed: 12/12/2022] Open
Abstract
Therapeutic strategies that target leukemic stem cells (LSC) provide potential advantages in the treatment of chronic myeloid leukemia (CML). Here we showed that selective blockade of plasminogen activator inhibitor-1 (PAI-1) enhances the susceptibility of CML-LSC to tyrosine kinase inhibitor (TKI), which facilitates the eradication of CML-LSC and leads to sustained remission of the disease. We demonstrated for the first time that the TGF-−PAI-1 axis was selectively augmented in CMLLSC in the bone marrow (BM), thereby protecting CML-LSC from TKI treatment. Furthermore, the combined administration of the TKI imatib plus a PAI-1 inhibitor, in a mouse model of CML, significantly enhanced the eradication of CML cells in the BM and prolonged the survival of CML mice. The combined therapy of imatinib and a PAI-1 inhibitor prevented the recurrence of CML-like disease in serially transplanted recipients, indicating the elimination of CML-LSC. Interestingly, PAI-1 inhibitor treatment augmented membrane-type matrix metalloprotease-1 (MT1-MMP)-dependent motility of CML-LSC, and the anti-CML effect of PAI-1 inhibitor was extinguished by the neutralizing antibody for MT1-MMP, underlining the mechanistic importance of MT1-MMP. Our findings provide evidence of, and a rationale for, a novel therapeutic tactic, based on the blockade of PAI- 1 activity, for CML patients.
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Abstract
Fibroblast growth factor 23 (FGF23) is a phosphotropic hormone that belongs to a subfamily of endocrine FGFs with evolutionarily conserved functions in worms and fruit flies. FAM20C phosphorylates FGF23 post-translationally, targeting it to proteolysis through subtilisin-like proprotein convertase FURIN, resulting in secretion of FGF23 fragments. O-glycosylation of FGF23 through GALNT3 appears to prevent proteolysis, resulting in secretion of biologically active intact FGF23. In the circulation, FGF23 may undergo further processing by plasminogen activators. Crystal structures show that the ectodomain of the cognate FGF23 receptor FGFR1c binds with the ectodomain of the co-receptor alpha-KLOTHO. The KLOTHO-FGFR1c double heterodimer creates a high-affinity binding site for the FGF23 C-terminus. The topology of FGF23 deviates from that of paracrine FGFs, resulting in poor affinity for heparan sulphate, which may explain why FGF23 diffuses freely in the bone matrix to enter the bloodstream following its secretion by cells of osteoblastic lineage. Intact FGF23 signalling by this canonical pathway activates FRS2/RAS/RAF/MEK/ERK1/2. It reduces serum phosphate by inhibiting 1,25-dihydroxyvitamin D synthesis, suppressing intestinal phosphate absorption, and by downregulating the transporters NPT2a and NPT2c, suppressing phosphate reabsorption in the proximal tubules. The physiological role of FGF23 fragments, which may be inhibitory, remains unclear. Pharmacological and genetic activation of canonical FGF23 signalling causes hypophosphatemic disorders, while its inhibition results in hyperphosphatemic disorders. Non-canonical FGF23 signalling through binding and activation of FGFR3/FGFR4/calcineurin/NFAT in an alpha-KLOTHO-independent fashion mainly occurs at extremely elevated circulating FGF23 levels and may contribute to mortality due to cardiovascular disease and left ventricular hypertrophy in chronic kidney disease.
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Affiliation(s)
- Bryan B Ho
- Department of Internal Medicine, Section Endocrinology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Clemens Bergwitz
- Department of Internal Medicine, Section Endocrinology, Yale University School of Medicine, New Haven, Connecticut, USA
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16
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Abstract
The rapid rise in circulating fibroblast growth factor 23 (FGF23) associated with kidney injury results in calcitriol deficiency, altered calcium homeostasis, and secondary hyperparathyroidism, and may contribute to cardiovascular complications and death. However, the mechanisms of increased FGF23 in states of kidney injury remain unclear. In this issue of the JCI, Simic et al. screened plasma taken from the renal vein of patients undergoing cardiac catheterization and identified glycerol-3-phosphate (G-3-P) as the most significant correlate of simultaneous arterial FGF23 levels. When G-3-P was administered to mice, FGF23 production increased in bone. In a series of elegant mouse studies, the authors discovered a pathway linking increased G-3-P to increased FGF23 via increases in lysophosphatidic acid (LPA), which activates the LPA receptor 1 in FGF23-secreting cells in the bone and bone marrow. Although the authors present human data that broadly support the results from the mouse models, further research is needed to determine whether targeting the G-3-P/FGF23 pathway has the potential to modify FGF23-related complications in the clinic.
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Affiliation(s)
| | - Myles Wolf
- Division of Nephrology, Department of Medicine, and.,Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina, USA
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17
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Agoro R, Ni P, Noonan ML, White KE. Osteocytic FGF23 and Its Kidney Function. Front Endocrinol (Lausanne) 2020; 11:592. [PMID: 32982979 PMCID: PMC7485387 DOI: 10.3389/fendo.2020.00592] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 07/20/2020] [Indexed: 12/16/2022] Open
Abstract
Osteocytes, which represent up to 95% of adult skeletal cells, are deeply embedded in bone. These cells exhibit important interactive abilities with other bone cells such as osteoblasts and osteoclasts to control skeletal formation and resorption. Beyond this local role, osteocytes can also influence the function of distant organs due to the presence of their sophisticated lacunocanalicular system, which connects osteocyte dendrites directly to the vasculature. Through these networks, osteocytes sense changes in circulating metabolites and respond by producing endocrine factors to control homeostasis. One critical function of osteocytes is to respond to increased blood phosphate and 1,25(OH)2 vitamin D (1,25D) by producing fibroblast growth factor-23 (FGF23). FGF23 acts on the kidneys through partner fibroblast growth factor receptors (FGFRs) and the co-receptor Klotho to promote phosphaturia via a downregulation of phosphate transporters, as well as the control of vitamin D metabolizing enzymes to reduce blood 1,25D. In the first part of this review, we will explore the signals involved in the positive and negative regulation of FGF23 in osteocytes. In the second portion, we will bridge bone responses with the review of current knowledge on FGF23 endocrine functions in the kidneys.
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Affiliation(s)
- Rafiou Agoro
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Pu Ni
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Megan L. Noonan
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Kenneth E. White
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
- Medicine/Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN, United States
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18
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Lacroix JS, Urena-Torres P. Potentielle application de l’axe fibroblast growth factor 23-Klotho dans la maladie rénale chronique. Nephrol Ther 2020; 16:83-92. [DOI: 10.1016/j.nephro.2019.05.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Accepted: 05/19/2019] [Indexed: 12/17/2022]
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19
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Fibroblast growth factor 23 and α-Klotho co-dependent and independent functions. Curr Opin Nephrol Hypertens 2019; 28:16-25. [PMID: 30451736 DOI: 10.1097/mnh.0000000000000467] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
PURPOSE OF REVIEW The current review examines what is known about the FGF-23/α-Klotho co-dependent and independent pathophysiological effects, and whether FGF-23 and/or α-Klotho are potential therapeutic targets. RECENT FINDINGS FGF-23 is a hormone derived mainly from bone, and α-Klotho is a transmembrane protein. Together they form a trimeric signaling complex with FGFRs in target tissues to mediate the physiological functions of FGF-23. Local and systemic factors control FGF-23 release from osteoblast/osteocytes in bone, and circulating FGF-23 activates FGFR/α-Klotho complexes in kidney proximal and distal renal tubules to regulate renal phosphate excretion, 1,25 (OH)2D metabolism, sodium and calcium reabsorption, and ACE2 and α-Klotho expression. The resulting bone-renal-cardiac-immune networks provide a new understanding of bone and mineral homeostasis, as well as identify other biological effects FGF-23. Direct FGF-23 activation of FGFRs in the absence of α-Klotho is proposed to mediate cardiotoxic and adverse innate immune effects of excess FGF-23, particularly in chronic kidney disease, but this FGF-23, α-Klotho-independent signaling is controversial. In addition, circulating soluble Klotho (sKl) released from the distal tubule by ectodomain shedding is proposed to have beneficial health effects independent of FGF-23. SUMMARY Separation of FGF-23 and α-Klotho independent functions has been difficult in mammalian systems and understanding FGF-23/α-Klotho co-dependent and independent effects are incomplete. Antagonism of FGF-23 is important in treatment of hypophosphatemic disorders caused by excess FGF-23, but its role in chronic kidney disease is uncertain. Administration of recombinant sKl is an unproven therapeutic strategy that theoretically could improve the healt span and lifespan of patients with α-Klotho deficiency.
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20
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Bär L, Stournaras C, Lang F, Föller M. Regulation of fibroblast growth factor 23 (FGF23) in health and disease. FEBS Lett 2019; 593:1879-1900. [PMID: 31199502 DOI: 10.1002/1873-3468.13494] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Revised: 03/26/2019] [Accepted: 03/27/2019] [Indexed: 12/19/2022]
Abstract
Fibroblast growth factor 23 (FGF23) is mainly produced in the bone and, upon secretion, forms a complex with a FGF receptor and coreceptor αKlotho. FGF23 can exert several endocrine functions, such as inhibiting renal phosphate reabsorption and 1,25-dihydroxyvitamin D3 production. Moreover, it has paracrine activities on several cell types, including neutrophils and hepatocytes. Klotho and Fgf23 deficiencies result in pathologies otherwise encountered in age-associated diseases, mainly as a result of hyperphosphataemia-dependent calcification. FGF23 levels are also perturbed in the plasma of patients with several disorders, including kidney or cardiovascular diseases. Here, we review mechanisms controlling FGF23 production and discuss how FGF23 regulation is perturbed in disease.
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Affiliation(s)
- Ludmilla Bär
- Institute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Christos Stournaras
- Institute of Biochemistry, University of Crete Medical School, Heraklion, Greece
| | - Florian Lang
- Institute of Physiology, University of Tübingen, Germany
| | - Michael Föller
- Institute of Physiology, University of Hohenheim, Stuttgart, Germany
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21
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Abstract
Acute kidney injury (AKI) is associated with many of the same mineral metabolite abnormalities that are observed in chronic kidney disease. These include increased circulating levels of the osteocyte-derived, vitamin D-regulating hormone, fibroblast growth factor 23 (FGF23), and decreased renal expression of klotho, the co-receptor for FGF23. Recent data have indicated that increased FGF23 and decreased klotho levels in the blood and urine could serve as novel predictive biomarkers of incident AKI, or as novel prognostic biomarkers of adverse outcomes in patients with established AKI. In addition, because FGF23 and klotho exert numerous classic as well as off-target effects on a variety of organ systems, targeting their dysregulation in AKI may represent a unique opportunity for therapeutic intervention. We review the pathophysiology, kinetics, and regulation of FGF23 and klotho in animal and human studies of AKI, and we discuss the challenges and opportunities involved in targeting FGF23 and klotho therapeutically.
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Affiliation(s)
- Marta Christov
- Department of Medicine, New York Medical College, Valhalla, NY.
| | - Javier A Neyra
- Division of Nephrology, Bone and Mineral Metabolism, Department of Internal Medicine, University of Kentucky, Lexington, KY; Division of Nephrology, Department of Internal Medicine, University of Texas Southwestern, Dallas, TX
| | - Sanjeev Gupta
- Department of Medicine, New York Medical College, Valhalla, NY
| | - David E Leaf
- Division of Renal Medicine, Brigham and Women's Hospital, Boston, MA
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22
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Zhang C, Ma P, Zhao Z, Jiang N, Lian D, Huo P, Yang H. miRNA‑mRNA regulatory network analysis of mesenchymal stem cell treatment in cisplatin‑induced acute kidney injury identifies roles for miR‑210/Serpine1 and miR‑378/Fos in regulating inflammation. Mol Med Rep 2019; 20:1509-1522. [PMID: 31257474 PMCID: PMC6625446 DOI: 10.3892/mmr.2019.10383] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Accepted: 03/11/2019] [Indexed: 12/26/2022] Open
Abstract
The present study aimed to identify microRNAs (miRNAs) that may be crucial for the mechanism of mesenchymal stem cell (MSC) treatment in cisplatin-induced acute kidney injury (AKI) and to investigate other potential drugs that may have a similar function. Transcriptomics (GSE85957) and miRNA expression (GSE66761) datasets were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) were identified using the linear models for microarray data method and mRNA targets of DEMs were predicted using the miRWalk2.0 database. The crucial DEGs were screened by constructing a protein-protein interaction (PPI) network and module analysis. Functions of target genes were analyzed using the database for annotation, visualization and integrated discovery. Small molecule drugs were predicted using the connectivity map database. As a result, 5 DEMs were identified to be shared and oppositely expressed in comparisons between AKI model and control groups, and between MSC treatment and AKI model groups. The 103 DEGs were overlapped with the target genes of 5 common DEMs, and the resulting list was used for constructing the miRNA-mRNA regulatory network, including rno-miR-210/Serpine1 and rno-miR-378/Fos. Serpine1 (degree=17) and Fos (degree=42) were predicted to be hub genes according to the topological characteristic of degree in the PPI network. Function analysis indicated Serpine1 and Fos may be inflammation-related. Furthermore, gliclazide was suggested to be a potential drug for the treatment of AKI because the enrichment score was the closest to −1 (−0.9). In conclusion, it can be speculated that gliclazide may have a similar mechanism to MSC as a potential therapeutic agent for cisplatin-induced AKI, by regulating miR-210/Serpine1 and miR-378-/Fos-mediated inflammation and cell apoptosis.
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Affiliation(s)
- Chunmei Zhang
- Intensive Care Unit of The Emergency Department, China‑Japan Union Hospital, Jilin University, Changchun, Jilin 130031, P.R. China
| | - Piyong Ma
- Intensive Care Unit of The Emergency Department, China‑Japan Union Hospital, Jilin University, Changchun, Jilin 130031, P.R. China
| | - Zhongyan Zhao
- Intensive Care Unit of The Emergency Department, China‑Japan Union Hospital, Jilin University, Changchun, Jilin 130031, P.R. China
| | - Nan Jiang
- Intensive Care Unit of The Emergency Department, China‑Japan Union Hospital, Jilin University, Changchun, Jilin 130031, P.R. China
| | - Dede Lian
- Intensive Care Unit of The Emergency Department, China‑Japan Union Hospital, Jilin University, Changchun, Jilin 130031, P.R. China
| | - Pengfei Huo
- Intensive Care Unit of The Emergency Department, China‑Japan Union Hospital, Jilin University, Changchun, Jilin 130031, P.R. China
| | - Hailing Yang
- Emergency Department, China‑Japan Union Hospital, Jilin University, Changchun, Jilin 130031, P.R. China
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23
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Abstract
PURPOSE OF REVIEW The phosphaturic hormone FGF23 is produced primarily in osteoblasts/osteocytes and is known to respond to increases in serum phosphate and 1,25(OH)2 vitamin D (1,25D). Novel regulators of FGF23 were recently identified, and may help explain the pathophysiologies of several diseases. This review will focus on recent studies examining the synthesis and actions of FGF23. RECENT FINDINGS The synthesis of FGF23 in response to 1,25D is similar to other steroid hormone targets, but the cellular responses to phosphate remain largely unknown. The activity of intracellular processing genes control FGF23 glycosylation and phosphorylation, providing critical functions in determining the serum levels of bioactive FGF23. The actions of FGF23 largely occur through its co-receptor αKlotho (KL) under normal circumstances, but FGF23 has KL-independent activity during situations of high concentrations. SUMMARY Recent work regarding FGF23 synthesis and bioactivity, as well as considerations for diseases of altered phosphate balance will be reviewed.
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Affiliation(s)
- Megan L Noonan
- Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Kenneth E White
- Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
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24
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Hu MC, Shi M, Moe OW. Role of αKlotho and FGF23 in regulation of type II Na-dependent phosphate co-transporters. Pflugers Arch 2018; 471:99-108. [PMID: 30506274 DOI: 10.1007/s00424-018-2238-5] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Revised: 11/16/2018] [Accepted: 11/18/2018] [Indexed: 11/26/2022]
Abstract
Alpha-Klotho is a member of the Klotho family consisting of two other single-pass transmembrane proteins: βKlotho and γKlotho; αKlotho has been shown to circulate in the blood. Fibroblast growth factor (FGF)23 is a member of the FGF superfamily of 22 genes/proteins. αKlotho serves as a co-receptor with FGF receptors (FGFRs) to provide a receptacle for physiological FGF23 signaling including regulation of phosphate metabolism. The extracellular domain of transmembrane αKlotho is shed by secretases and released into blood circulation (soluble αKlotho). Soluble αKlotho has both FGF23-independent and FGF23-dependent roles in phosphate homeostasis by modulating intestinal phosphate absorption, urinary phosphate excretion, and phosphate distribution into bone in concerted interaction with other calciophosphotropic hormones such as PTH and 1,25-(OH)2D. The direct role of αKlotho and FGF23 in the maintenance of phosphate homeostasis is partly mediated by modulation of type II Na+-dependent phosphate co-transporters in target organs. αKlotho and FGF23 are principal phosphotropic hormones, and the manipulation of the αKlotho-FGF23 axis is a novel therapeutic strategy for genetic and acquired phosphate disorders and for conditions with FGF23 excess and αKlotho deficiency such as chronic kidney disease.
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Affiliation(s)
- Ming Chang Hu
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA.
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
| | - Mingjun Shi
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA
| | - Orson W Moe
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA.
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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25
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Bon N, Frangi G, Sourice S, Guicheux J, Beck-Cormier S, Beck L. Phosphate-dependent FGF23 secretion is modulated by PiT2/Slc20a2. Mol Metab 2018; 11:197-204. [PMID: 29551636 PMCID: PMC6001877 DOI: 10.1016/j.molmet.2018.02.007] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2017] [Revised: 02/12/2018] [Accepted: 02/15/2018] [Indexed: 12/19/2022] Open
Abstract
OBJECTIVE The canonical role of the bone-derived fibroblast growth factor 23 (Fgf23) is to regulate the serum inorganic phosphate (Pi) level. As part of a feedback loop, serum Pi levels control Fgf23 secretion through undefined mechanisms. We recently showed in vitro that the two high-affinity Na+-Pi co-transporters PiT1/Slc20a1 and PiT2/Slc20a2 were required for mediating Pi-dependent signaling. Here, we addressed the contribution of PiT1 and PiT2 to the regulation of Fgf23 secretion. METHODS To this aim, we used PiT2 KO and DMP1Cre; PiT1lox/lox fed Pi-modified diets, as well as ex vivo isolated long bone shafts. Fgf23 secretion and expression of Pi homeostasis-related genes were assessed. RESULTS In vivo, PiT2 KO mice responded inappropriately to low-Pi diets, displaying abnormally normal serum levels of intact Fgf23. Despite the high iFgf23 level, serum Pi levels remained unaffected, an effect that may relate to lower αKlotho expression in the kidney. Moreover, consistent with a role of PiT2 as a possible endocrine Pi sensor, the iFGF23/cFGF23 ratios were suppressed in PiT2 KO mice, irrespective of the Pi loads. While deletion of PiT1 in osteocytes using the DMP1-Cre mice was inefficient, adenovirus-mediated deletion of PiT1 in isolated long bone shafts suggested that PiT1 does not contribute to Pi-dependent regulation of Fgf23 secretion. In contrast, using isolated bone shafts from PiT2 KO mice, we showed that PiT2 was necessary for the appropriate Pi-dependent secretion of Fgf23, independently from possible endocrine regulatory loops. CONCLUSIONS Our data provide initial mechanistic insights underlying the Pi-dependent regulation of Fgf23 secretion in identifying PiT2 as a potential player in this process, at least in high Pi conditions. Targeting PiT2, therefore, could improve excess FGF23 in hyperphosphatemic conditions such as chronic kidney disease.
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Affiliation(s)
- Nina Bon
- Inserm, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, Nantes, F-44042, France; Université de Nantes, UFR Odontologie, Nantes, F-44042, France
| | - Giulia Frangi
- Inserm, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, Nantes, F-44042, France; Université de Nantes, UFR Odontologie, Nantes, F-44042, France
| | - Sophie Sourice
- Inserm, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, Nantes, F-44042, France; Université de Nantes, UFR Odontologie, Nantes, F-44042, France
| | - Jérôme Guicheux
- Inserm, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, Nantes, F-44042, France; Université de Nantes, UFR Odontologie, Nantes, F-44042, France; CHU Nantes, PHU 4 OTONN, Nantes, F-44042, France
| | - Sarah Beck-Cormier
- Inserm, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, Nantes, F-44042, France; Université de Nantes, UFR Odontologie, Nantes, F-44042, France
| | - Laurent Beck
- Inserm, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, Nantes, F-44042, France; Université de Nantes, UFR Odontologie, Nantes, F-44042, France.
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