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Liu L, Wu P, Wei Y, Lu M, Ge H, Wang P, Sun J, Horng T, Liu X, Shen X, Sun L, Xi Y. TWEAK-Fn14 signaling protects mice from pulmonary fibrosis by inhibiting fibroblast activation and recruiting pro-regenerative macrophages. Cell Rep 2025; 44:115220. [PMID: 39827460 DOI: 10.1016/j.celrep.2024.115220] [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: 04/08/2024] [Revised: 11/11/2024] [Accepted: 12/26/2024] [Indexed: 01/22/2025] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by excess accumulation of the extracellular matrix (ECM). The role of macrophage-fibroblast crosstalk in lung fibrogenesis is incompletely understood. Here we found that fibroblast growth factor-inducible molecule 14 (Fn14), the receptor for tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is highly induced in myofibroblasts in the lungs of IPF patients and the bleomycin-induced lung fibrosis model. TWEAK-Fn14 signaling inhibits fibroblast activation and ECM synthesis and induces chemokine expression to recruit monocytes/macrophages into the lung. Fn14 deficiency increases ECM production and impairs macrophage infiltration and differentiation, leading to exacerbated lung fibrosis and impaired alveolar regeneration in a bleomycin model. Interestingly, Fn14 deficiency diminishes an injury-induced SiglecF- CD11b- MHCIIlo intermediate macrophage (IntermM) subpopulation, which promotes alveolar type II (AT2) cell proliferation in organoid cultures. These results collectively demonstrate a protective role of TWEAK-Fn14 signaling in lung fibrosis, highlighting the complexities and multilayered regulation of macrophage-fibroblast crosstalk.
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Affiliation(s)
- Li Liu
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University, Shanghai 201210, China
| | - Pei Wu
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University, Shanghai 201210, China
| | - Yuqi Wei
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Meng Lu
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University, Shanghai 201210, China
| | - Haiyan Ge
- Department of Pulmonary and Critical Care Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China
| | - Ping Wang
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University, Shanghai 201210, China
| | - Jianlong Sun
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University, Shanghai 201210, China
| | - Tiffany Horng
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Xiucheng Liu
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.
| | - Xiaoyong Shen
- Department of Thoracic Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China.
| | - Lingyun Sun
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China.
| | - Ying Xi
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University, Shanghai 201210, China.
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Maqueda‐Zelaya F, Valiño‐Rivas L, Milián A, Gutiérrez S, Aceña JL, Garcia‐Marin J, Sánchez‐Niño MD, Vaquero JJ, Ortiz A. Identification and study of new NF-κB-inducing kinase ligands derived from the imidazolone scaffold. Arch Pharm (Weinheim) 2025; 358:e2400614. [PMID: 39604268 PMCID: PMC11704032 DOI: 10.1002/ardp.202400614] [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: 07/29/2024] [Revised: 11/05/2024] [Accepted: 11/11/2024] [Indexed: 11/29/2024]
Abstract
Chronic kidney disease (CKD) is a growing health concern, projected to be a major cause of death by 2040, due to an increasing risk of acute kidney injury (AKI). Systems biology-derived data suggest that the unmet need for an orally available drug to treat AKI and improve CKD outcomes may be addressed by targeting kidney inflammation and, specifically, nuclear factor κB-inducing kinase (NIK), a key signaling molecule that activates the noncanonical nuclear factor κB (NF-κB) pathway. We have prepared and identified a small family of imidazolone derivatives that bind NIK and inhibit the noncanonical NF-κB activation pathway. The introduction of heterocyclic substituents in position 2 of the imidazolone core provides compounds with affinity against human NIK. Three candidates, with best affinity profile, were tested in phenotypic experiments of noncanonical NF-κB activation, confirming that the derivative bearing the 4-pyridyl ring can inhibit the processing of NFκB p100 to NFkB2 p52, which is NIK-dependent in cultured kidney tubular cells. Finally, exhaustive docking calculations combined with molecular dynamics studies led us to propose a theoretical binding mode and rationalize affinity measures, in which the aminopyridine motif is a key anchoring point to the hinge region thanks to several hydrogen bonds and the interaction of heterocyclic rings in position 2 with Ser476 and Lys482. Our result will pave the way for the development of potential drug candidates targeting NIK in the context of CKD.
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Affiliation(s)
- Francisco Maqueda‐Zelaya
- Departamento de Química Orgánica y Química Inorgánica, Instituto de Investigación Química “Andrés M. Del Río” (IQAR)Universidad de Alcalá (IRYCIS)Alcalá de Henares, MadridSpain
| | - Lara Valiño‐Rivas
- Departamento de Nefrología e HipertensiónIIS‐Fundación Jiménez Díaz UAMMadridSpain
| | - Ana Milián
- Departamento de Química Orgánica y Química Inorgánica, Instituto de Investigación Química “Andrés M. Del Río” (IQAR)Universidad de Alcalá (IRYCIS)Alcalá de Henares, MadridSpain
| | - Sara Gutiérrez
- Departamento de Química Orgánica y Química Inorgánica, Instituto de Investigación Química “Andrés M. Del Río” (IQAR)Universidad de Alcalá (IRYCIS)Alcalá de Henares, MadridSpain
| | - José Luis Aceña
- Departamento de Química Orgánica y Química Inorgánica, Instituto de Investigación Química “Andrés M. Del Río” (IQAR)Universidad de Alcalá (IRYCIS)Alcalá de Henares, MadridSpain
- RICORS2040MadridSpain
| | - Javier Garcia‐Marin
- Departamento de Química Orgánica y Química Inorgánica, Instituto de Investigación Química “Andrés M. Del Río” (IQAR)Universidad de Alcalá (IRYCIS)Alcalá de Henares, MadridSpain
- RICORS2040MadridSpain
| | - Mª Dolores Sánchez‐Niño
- Departamento de Nefrología e HipertensiónIIS‐Fundación Jiménez Díaz UAMMadridSpain
- RICORS2040MadridSpain
- Departamento de Farmacología, Facultad de MedicinaUniversidad Autónoma de MadridMadridSpain
| | - Juan J. Vaquero
- Departamento de Química Orgánica y Química Inorgánica, Instituto de Investigación Química “Andrés M. Del Río” (IQAR)Universidad de Alcalá (IRYCIS)Alcalá de Henares, MadridSpain
- RICORS2040MadridSpain
| | - Alberto Ortiz
- Departamento de Nefrología e HipertensiónIIS‐Fundación Jiménez Díaz UAMMadridSpain
- RICORS2040MadridSpain
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3
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Mohamed RH, Abdelrahim DS, Hay NHA, Fawzy NM, M DKM, Yehia DAY, AbdelMaksoud OM, Tamim YM. The role of protein prenylation inhibition through targeting FPPS by zoledronic acid in the prevention of renal fibrosis in rats. Sci Rep 2024; 14:18283. [PMID: 39112499 PMCID: PMC11306734 DOI: 10.1038/s41598-024-68303-z] [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: 04/19/2024] [Accepted: 07/22/2024] [Indexed: 08/10/2024] Open
Abstract
Renal fibrosis (RF) represents the most widespread pathological condition in chronic kidney disease (CKD). Recently, protein prenylation has been implicated in the fibrosis's progression. The research examined the renoprotective effect of zoledronic acid (ZA) (50 µg/kg/week) in a rat model of carbon tetrachloride (CCl4)-induced RF through targeting protein prenylation. Forty Wistar male rats were split up into the control group, vehicle-treated group, model-RF group, and RF-ZA group. Mean arterial blood pressure (MBP), BUN, serum creatinine, and urine albumin-creatinine ratio (uACR), protein levels of farnesyl pyrophosphate (FPP), tumour necrosis factor-alpha (TNF-α), transforming growth factor-β (TGF-β), and malondialdehyde (MDA), and catalase and gene expression of farnesyl pyrophosphate synthase (FPPS) and nuclear factor-kB (NF-κB) were measured. Immunohistochemical staining for renal interleukin-6 (IL-6), α-smooth muscle actin (α-SMA), and caspase-3, as well as histopathological alterations, were assessed. ZA considerably ceased the reduction in MBP, markedly reduced uACR, serum creatinine, BUN, and expression of FPPS, FPP, NF-κB, TGF-β, TNF-α, and MDA, and significantly increased catalase levels compared to the model-RF rats. ZA ameliorated the CCl4-induced histopathological alterations and suppressed the expression of caspase-3, α-SMA, and IL-6. In conclusion, ZA preserved renal function and prevented renal fibrosis in a rat model. These were achieved through targeting protein prenylation mainly by inhibiting FPPS.
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Affiliation(s)
- Reham Hussein Mohamed
- Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Abbasia, Cairo, Egypt.
| | - Dina S Abdelrahim
- Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Abbasia, Cairo, Egypt
- Department of Pharmacology, Faculty of Medicine, Modern Technology & Information University, Cairo, Egypt
| | - Nesma Hussein Abdel Hay
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Nesma Mohamed Fawzy
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Doaa Karem M M
- Department of Histology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | | | - Omnia M AbdelMaksoud
- Department of Medical Physiology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Yomna M Tamim
- Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Abbasia, Cairo, Egypt
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Córdoba-David G, García-Giménez J, Cardoso Castelo-Branco R, Carrasco S, Cannata P, Ortiz A, Ramos AM. Crosstalk between TBK1/IKKε and the type I interferon pathway contributes to tubulointerstitial inflammation and kidney tubular injury. Front Pharmacol 2022; 13:987979. [PMID: 36386242 PMCID: PMC9647636 DOI: 10.3389/fphar.2022.987979] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Accepted: 08/22/2022] [Indexed: 09/01/2023] Open
Abstract
The type I interferon (TI-IFN) pathway regulates innate immunity, inflammation, and apoptosis during infection. However, the contribution of the TI-IFN pathway or upstream signaling pathways to tubular injury in kidney disease is poorly understood. Upon observing evidence of activation of upstream regulators of the TI-IFN pathway in a transcriptomics analysis of murine kidney tubulointerstitial injury, we have now addressed the impact of the TI-IFN and upstream signaling pathways on kidney tubulointerstitial injury. In cultured tubular cells and kidney tissue, IFNα/β binding to IFNAR activated the TI-IFN pathway and recruited antiviral interferon-stimulated genes (ISG) and NF-κB-associated proinflammatory responses. TWEAK and lipopolysaccharide (LPS) signaled through TBK1/IKKε and IRF3 to activate both ISGs and NF-κB. In addition, TWEAK recruited TLR4 to stimulate TBK1/IKKε-dependent ISG and inflammatory responses. Dual pharmacological inhibition of TBK1/IKKε with amlexanox decreased TWEAK- or LPS-induced ISG and cytokine responses, as well as cell death induced by a complex inflammatory milieu that included TWEAK. TBK1 or IRF3 siRNA prevented the TWEAK-induced ISG and inflammatory gene expression while IKKε siRNA did not. In vivo, kidney IFNAR and IFNβ were increased in murine LPS and folic acid nephrotoxicity while IFNAR was increased in human kidney biopsies with tubulointerstitial damage. Inhibition of TBK1/IKKε with amlexanox or IFNAR neutralization decreased TI-IFN pathway activation and protected from kidney injury induced by folic acid or LPS. In conclusion, TI-IFNs, TWEAK, and LPS engage interrelated proinflammatory and antiviral responses in tubular cells. Moreover, inhibition of TBK1/IKKε with amlexanox, and IFNAR targeting, may protect from tubulointerstitial kidney injury.
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Affiliation(s)
- Gina Córdoba-David
- Department of Nephrology and Hypertension, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain
| | - Jorge García-Giménez
- Department of Nephrology and Hypertension, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain
| | | | - Susana Carrasco
- Department of Nephrology and Hypertension, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain
- RICORS 2040, Madrid, Spain
| | - Pablo Cannata
- Department of Pathology, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain
| | - Alberto Ortiz
- Department of Nephrology and Hypertension, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain
- RICORS 2040, Madrid, Spain
- Department of Medicine, Universidad Autónoma de Madrid, Madrid, Spain
| | - Adrián M. Ramos
- Department of Nephrology and Hypertension, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain
- RICORS 2040, Madrid, Spain
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Valiño-Rivas L, Cuarental L, Ceballos MI, Pintor-Chocano A, Perez-Gomez MV, Sanz AB, Ortiz A, Sanchez-Niño MD. Growth differentiation factor-15 preserves Klotho expression in acute kidney injury and kidney fibrosis. Kidney Int 2022; 101:1200-1215. [PMID: 35337892 DOI: 10.1016/j.kint.2022.02.028] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 02/07/2022] [Accepted: 02/16/2022] [Indexed: 02/07/2023]
Abstract
Growth differentiation factor-15 (GDF15) is a member of the GDF subfamily with potential kidney protective functions. Here, we explored the impact of GDF15 on the expression of the kidney protective factor Klotho in models of acute kidney injury and kidney fibrosis in mice. GDF15 was the most upregulated GDF family gene in experimental toxic acute kidney injury and in kidney fibrosis transcriptomics. GDF15 function was explored in toxic acute kidney injury in genetically modified mice and following treatment with GDF15. Gdf15-deficient mice developed more severe toxic acute kidney injury (folic acid or cisplatin) while GDF15 overexpression or GDF15 administration were protective. Kidney expression of Klotho was more severely depressed in Gdf15-deficient mice and was preserved by GDF15 overexpression or GDF15 treatment. Moreover, increased plasma calcitriol levels inversely correlated with kidney Klotho across models with diverse levels of GDF15 availability. Kidney fibrosis induced by unilateral ureteral obstruction was more severe in Gdf15-deficient mice while GDF15 overexpression decreased kidney injury and preserved Klotho expression. GDF15 increased Klotho expression in vivo in healthy mice, in cultured tubular cells, and prevented Klotho downregulation by inflammatory factors in tubular cells by preventing transcription factor NF-ĸB activation. Thus, spontaneous increased kidney expression of endogenous GDF15 is not enough to prevent kidney injury, but further increments in GDF15 are kidney protecting and preserve expression of the kidney protective factor Klotho within the kidney in acute and chronic settings.
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Affiliation(s)
- Lara Valiño-Rivas
- Department of Nephrology and Hypertension. IIS-Fundacion Jimenez Diaz, School of Medicine, Universidad Autonoma de Madrid and REDINREN and FRIAT, Madrid, Spain
| | - Leticia Cuarental
- Department of Nephrology and Hypertension. IIS-Fundacion Jimenez Diaz, School of Medicine, Universidad Autonoma de Madrid and REDINREN and FRIAT, Madrid, Spain
| | - Maria I Ceballos
- Department of Nephrology and Hypertension. IIS-Fundacion Jimenez Diaz, School of Medicine, Universidad Autonoma de Madrid and REDINREN and FRIAT, Madrid, Spain
| | - Arancha Pintor-Chocano
- Department of Nephrology and Hypertension. IIS-Fundacion Jimenez Diaz, School of Medicine, Universidad Autonoma de Madrid and REDINREN and FRIAT, Madrid, Spain
| | - Maria Vanessa Perez-Gomez
- Department of Nephrology and Hypertension. IIS-Fundacion Jimenez Diaz, School of Medicine, Universidad Autonoma de Madrid and REDINREN and FRIAT, Madrid, Spain
| | - Ana B Sanz
- Department of Nephrology and Hypertension. IIS-Fundacion Jimenez Diaz, School of Medicine, Universidad Autonoma de Madrid and REDINREN and FRIAT, Madrid, Spain
| | - Alberto Ortiz
- Department of Nephrology and Hypertension. IIS-Fundacion Jimenez Diaz, School of Medicine, Universidad Autonoma de Madrid and REDINREN and FRIAT, Madrid, Spain
| | - Maria Dolores Sanchez-Niño
- Department of Nephrology and Hypertension. IIS-Fundacion Jimenez Diaz, School of Medicine, Universidad Autonoma de Madrid and REDINREN and FRIAT, Madrid, Spain; Department of Pharmacology, Universidad Autonoma de Madrid, Madrid, Spain.
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6
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Martin-Sanchez D, Guerrero-Mauvecin J, Fontecha-Barriuso M, Mendez-Barbero N, Saiz ML, Lopez-Diaz AM, Sanchez-Niño MD, Carrasco S, Cannata-Ortiz P, Ruiz-Ortega M, Ortiz A, Sanz AB. Bone Marrow-Derived RIPK3 Mediates Kidney Inflammation in Acute Kidney Injury. J Am Soc Nephrol 2022; 33:357-373. [PMID: 35046131 PMCID: PMC8819996 DOI: 10.1681/asn.2021030383] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 12/04/2021] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND Receptor-interacting protein kinase 3 (RIPK3), a component of necroptosis pathways, may have an independent role in inflammation. It has been unclear which RIPK3-expressing cells are responsible for the anti-inflammatory effect of overall Ripk3 deficiency and whether Ripk3 deficiency protects against kidney inflammation occurring in the absence of tubular cell death. METHODS We used chimeric mice with bone marrow from wild-type and Ripk3-knockout mice to explore RIPK3's contribution to kidney inflammation in the presence of folic acid-induced acute kidney injury AKI (FA-AKI) or absence of AKI and kidney cell death (as seen in systemic administration of the cytokine TNF-like weak inducer of apoptosis [TWEAK]). RESULTS Tubular and interstitial cell RIPK3 expressions were increased in murine AKI. Ripk3 deficiency decreased NF-κB activation and kidney inflammation in FA-AKI but did not prevent kidney failure. In the chimeric mice, RIPK3-expressing bone marrow-derived cells were required for early inflammation in FA-AKI. The NLRP3 inflammasome was not involved in RIPK3's proinflammatory effect. Systemic TWEAK administration induced kidney inflammation in wild-type but not Ripk3-deficient mice. In cell cultures, TWEAK increased RIPK3 expression in bone marrow-derived macrophages and tubular cells. RIPK3 mediated TWEAK-induced NF-κB activation and inflammatory responses in bone marrow-derived macrophages and dendritic cells and in Jurkat T cells; however, in tubular cells, RIPK3 mediated only TWEAK-induced Il-6 expression. Furthermore, conditioned media from TWEAK-exposed wild-type macrophages, but not from Ripk3-deficient macrophages, promoted proinflammatory responses in cultured tubular cells. CONCLUSIONS RIPK3 mediates kidney inflammation independently from tubular cell death. Specific targeting of bone marrow-derived RIPK3 may limit kidney inflammation without the potential adverse effects of systemic RIPK3 targeting.
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Affiliation(s)
- Diego Martin-Sanchez
- Laboratorio de Nefrología Experimental, Instituto de Investigación Sanitaria-Fundacion Jimenez Diaz, Universidad Autonoma de Madrid, Madrid, Spain,Red de Investigacion Renal, Madrid, Spain
| | - Juan Guerrero-Mauvecin
- Laboratorio de Nefrología Experimental, Instituto de Investigación Sanitaria-Fundacion Jimenez Diaz, Universidad Autonoma de Madrid, Madrid, Spain
| | - Miguel Fontecha-Barriuso
- Laboratorio de Nefrología Experimental, Instituto de Investigación Sanitaria-Fundacion Jimenez Diaz, Universidad Autonoma de Madrid, Madrid, Spain,Red de Investigacion Renal, Madrid, Spain
| | - Nerea Mendez-Barbero
- Laboratorio de Patologia Vascular, Instituto de Investigación Sanitaria-Fundacion Jimenez Diaz, Universidad Autonoma de Madrid, Madrid, Spain,Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Madrid, Spain
| | - Maria Laura Saiz
- Translational Immunology Laboratory, Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain
| | - Ana M. Lopez-Diaz
- Laboratorio de Nefrología Experimental, Instituto de Investigación Sanitaria-Fundacion Jimenez Diaz, Universidad Autonoma de Madrid, Madrid, Spain
| | - Maria D. Sanchez-Niño
- Laboratorio de Nefrología Experimental, Instituto de Investigación Sanitaria-Fundacion Jimenez Diaz, Universidad Autonoma de Madrid, Madrid, Spain,Red de Investigacion Renal, Madrid, Spain,Department of Pharmacology, Universidad Autonoma de Madrid, Madrid, Spain
| | - Susana Carrasco
- Laboratorio de Nefrología Experimental, Instituto de Investigación Sanitaria-Fundacion Jimenez Diaz, Universidad Autonoma de Madrid, Madrid, Spain
| | - Pablo Cannata-Ortiz
- Department of Pathology, Instituto de Investigación Sanitaria-Fundacion Jimenez Diaz, Universidad Autonoma de Madrid, Madrid, Spain
| | - Marta Ruiz-Ortega
- Laboratorio de Nefrología Experimental, Instituto de Investigación Sanitaria-Fundacion Jimenez Diaz, Universidad Autonoma de Madrid, Madrid, Spain,Red de Investigacion Renal, Madrid, Spain,Department of Medicine, Universidad Autonoma de Madrid, Madrid, Spain
| | - Alberto Ortiz
- Laboratorio de Nefrología Experimental, Instituto de Investigación Sanitaria-Fundacion Jimenez Diaz, Universidad Autonoma de Madrid, Madrid, Spain,Red de Investigacion Renal, Madrid, Spain,Department of Medicine, Universidad Autonoma de Madrid, Madrid, Spain,Instituto Reina Sofia de Investigaciones Nefrologicas, Madrid, Spain
| | - Ana B. Sanz
- Laboratorio de Nefrología Experimental, Instituto de Investigación Sanitaria-Fundacion Jimenez Diaz, Universidad Autonoma de Madrid, Madrid, Spain,Red de Investigacion Renal, Madrid, Spain
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7
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Cordido A, Nuñez-Gonzalez L, Martinez-Moreno JM, Lamas-Gonzalez O, Rodriguez-Osorio L, Perez-Gomez MV, Martin-Sanchez D, Outeda P, Chiaravalli M, Watnick T, Boletta A, Diaz C, Carracedo A, Sanz AB, Ortiz A, Garcia-Gonzalez MA. TWEAK Signaling Pathway Blockade Slows Cyst Growth and Disease Progression in Autosomal Dominant Polycystic Kidney Disease. J Am Soc Nephrol 2021; 32:1913-1932. [PMID: 34155062 PMCID: PMC8455272 DOI: 10.1681/asn.2020071094] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 03/06/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND In autosomal dominant polycystic kidney disease (ADPKD), cyst development and enlargement lead to ESKD. Macrophage recruitment and interstitial inflammation promote cyst growth. TWEAK is a TNF superfamily (TNFSF) cytokine that regulates inflammatory responses, cell proliferation, and cell death, and its receptor Fn14 (TNFRSF12a) is expressed in macrophage and nephron epithelia. METHODS To evaluate the role of the TWEAK signaling pathway in cystic disease, we evaluated Fn14 expression in human and in an orthologous murine model of ADPKD. We also explored the cystic response to TWEAK signaling pathway activation and inhibition by peritoneal injection. RESULTS Meta-analysis of published animal-model data of cystic disease reveals mRNA upregulation of several components of the TWEAK signaling pathway. We also observed that TWEAK and Fn14 were overexpressed in mouse ADPKD kidney cysts, and TWEAK was significantly high in urine and cystic fluid from patients with ADPKD. TWEAK administration induced cystogenesis and increased cystic growth, worsening the phenotype in a murine ADPKD model. Anti-TWEAK antibodies significantly slowed the progression of ADPKD, preserved renal function, and improved survival. Furthermore, the anti-TWEAK cystogenesis reduction is related to decreased cell proliferation-related MAPK signaling, decreased NF-κB pathway activation, a slight reduction of fibrosis and apoptosis, and an indirect decrease in macrophage recruitment. CONCLUSIONS This study identifies the TWEAK signaling pathway as a new disease mechanism involved in cystogenesis and cystic growth and may lead to a new therapeutic approach in ADPKD.
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Affiliation(s)
- Adrian Cordido
- Group of Genetics and Developmental Biology of Renal Diseases, Nephrology Laboratory (N°11), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain,Genomic Medicine Group, Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain,RedInRen RETIC, Instituto de Salud Carlos III, Madrid, Spain
| | - Laura Nuñez-Gonzalez
- Group of Genetics and Developmental Biology of Renal Diseases, Nephrology Laboratory (N°11), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain,Genomic Medicine Group, Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain
| | - Julio M. Martinez-Moreno
- Department of Nephrology and Hypertension, Jiménez Díaz Foundation (Health Research Institute and Autonomous University of Madrid), Madrid, Spain
| | - Olaya Lamas-Gonzalez
- Group of Genetics and Developmental Biology of Renal Diseases, Nephrology Laboratory (N°11), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain
| | - Laura Rodriguez-Osorio
- RedInRen RETIC, Instituto de Salud Carlos III, Madrid, Spain,Department of Nephrology and Hypertension, Jiménez Díaz Foundation (Health Research Institute and Autonomous University of Madrid), Madrid, Spain
| | - Maria Vanessa Perez-Gomez
- RedInRen RETIC, Instituto de Salud Carlos III, Madrid, Spain,Department of Nephrology and Hypertension, Jiménez Díaz Foundation (Health Research Institute and Autonomous University of Madrid), Madrid, Spain
| | - Diego Martin-Sanchez
- RedInRen RETIC, Instituto de Salud Carlos III, Madrid, Spain,Department of Nephrology and Hypertension, Jiménez Díaz Foundation (Health Research Institute and Autonomous University of Madrid), Madrid, Spain
| | - Patricia Outeda
- Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| | - Marco Chiaravalli
- Division of Genetics and Cell Biology, Molecular Basis of Cystic Kidney Disorders Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS)–San Raffaele Scientific Institute, Milan, Italy
| | - Terry Watnick
- Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| | | | - Candido Diaz
- Group of Genetics and Developmental Biology of Renal Diseases, Nephrology Laboratory (N°11), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain,Nephrology Service, Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain
| | - Angel Carracedo
- Genomic Medicine Group, Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain,Galician Public Foundation of Genomic Medicine, Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain,Center in Network of Rare Diseases (CIBERER), University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Ana B. Sanz
- RedInRen RETIC, Instituto de Salud Carlos III, Madrid, Spain,Department of Nephrology and Hypertension, Jiménez Díaz Foundation (Health Research Institute and Autonomous University of Madrid), Madrid, Spain
| | - Alberto Ortiz
- RedInRen RETIC, Instituto de Salud Carlos III, Madrid, Spain,Department of Nephrology and Hypertension, Jiménez Díaz Foundation (Health Research Institute and Autonomous University of Madrid), Madrid, Spain
| | - Miguel A. Garcia-Gonzalez
- Group of Genetics and Developmental Biology of Renal Diseases, Nephrology Laboratory (N°11), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain,Genomic Medicine Group, Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain,RedInRen RETIC, Instituto de Salud Carlos III, Madrid, Spain,Galician Public Foundation of Genomic Medicine, Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain
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8
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Shi Y, Chen G, Teng J. Network-Based Expression Analyses and Experimental Verifications Reveal the Involvement of STUB1 in Acute Kidney Injury. Front Mol Biosci 2021; 8:655361. [PMID: 34262937 PMCID: PMC8273177 DOI: 10.3389/fmolb.2021.655361] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 06/07/2021] [Indexed: 12/15/2022] Open
Abstract
Acute kidney injury (AKI) is a severe and frequently observed condition associated with high morbidity and mortality. The molecular mechanisms underlying AKI have not been elucidated due to the complexity of the pathophysiological processes. Thus, we investigated the key biological molecules contributing to AKI based on the transcriptome profile. We analyzed the RNA sequencing data from 39 native human renal biopsy samples and 9 reference nephrectomies from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) and Gene Ontology (GO) analysis revealed that various GO terms were dysregulated in AKI. Gene set enrichment analysis (GSEA) highlighted dysregulated pathways, including "DNA replication," "chemokine signaling pathway," and "metabolic pathways." Furthermore, the protein-to-protein interaction (PPI) networks of the DEGs were constructed, and the hub genes were identified using Cytoscape. Moreover, weighted gene co-expression network analysis (WGCNA) was performed to validate the DEGs in AKI-related modules. Subsequently, the upregulated hub genes STUB1, SOCS1, and VHL were validated as upregulated in human AKI and a mouse cisplatin-induced AKI model. Moreover, the biological functions of STUB1 were investigated in renal tubular epithelial cells. Cisplatin treatment increased STUB1 expression in a dose-dependent manner at both the mRNA and protein levels. Knockdown of STUB1 by siRNA increased the expression of proapoptotic Bax and cleaved caspase-3 while decreasing antiapoptotic Bcl-2. In addition, silencing STUB1 increased the apoptosis of HK-2 cells and the proinflammatory cytokine production of IL6, TNFα, and IL1β induced by cisplatin. These results indicated that STUB1 may contribute to the initiation and progression of AKI by inducing renal tubular epithelial cell apoptosis and renal inflammation.
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Affiliation(s)
- Yanting Shi
- Department of Nephrology, Xiamen Branch, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Genwen Chen
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jie Teng
- Department of Nephrology, Xiamen Branch, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China
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9
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Wan S, Wan S, Jiao X, Cao H, Gu Y, Yan L, Zheng Y, Niu P, Shao F. Advances in understanding the innate immune-associated diabetic kidney disease. FASEB J 2021; 35:e21367. [PMID: 33508160 DOI: 10.1096/fj.202002334r] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 12/16/2020] [Accepted: 12/28/2020] [Indexed: 12/26/2022]
Abstract
Millions of human deaths occur annually due to chronic kidney disease, caused by diabetic kidney disease (DKD). Despite having effective drugs controlling the hyperglycemia and high blood pressure, the incidence of DKD is increasing, which indicates the need for the development of novel therapies to control DKD. In this article, we discussed the recent advancements in the basic innate immune mechanisms in renal tissues triggered under the diabetes environment, leading to the pathogenesis and progression of DKD. We also summarized the currently available innate immune molecules-targeting therapies tested against DKD in clinical and preclinical settings, and highlighted additional drug targets that could potentially be employed for the treatment of DKD. The improved understanding of the disease pathogenesis may open avenues for the development of novel therapies to rein in DKD, which consequently, can reduce morbidity and mortality in humans in the future.
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Affiliation(s)
- Shengfeng Wan
- Department of Nephrology, Henan Provincial Key Laboratory of Kidney Disease and Immunology, Henan Provincial People's Hospital (Zhengzhou University People's Hospital), Zhengzhou, China
| | - Shengkai Wan
- Department of Operations Management, Henan Provincial People's Hospital (Zhengzhou University People's Hospital), Zhengzhou, China
| | - Xiaojing Jiao
- Department of Nephrology, Henan Provincial Key Laboratory of Kidney Disease and Immunology, Henan Provincial People's Hospital (Zhengzhou University People's Hospital), Zhengzhou, China
| | - Huixia Cao
- Department of Nephrology, Henan Provincial Key Laboratory of Kidney Disease and Immunology, Henan Provincial People's Hospital (Zhengzhou University People's Hospital), Zhengzhou, China
| | - Yue Gu
- Department of Nephrology, Henan Provincial Key Laboratory of Kidney Disease and Immunology, Henan Provincial People's Hospital (Zhengzhou University People's Hospital), Zhengzhou, China
| | - Lei Yan
- Department of Nephrology, Henan Provincial Key Laboratory of Kidney Disease and Immunology, Henan Provincial People's Hospital (Zhengzhou University People's Hospital), Zhengzhou, China
| | - Yan Zheng
- Department of Nephrology, Henan Provincial Key Laboratory of Kidney Disease and Immunology, Henan Provincial People's Hospital (Zhengzhou University People's Hospital), Zhengzhou, China
| | - Peiyuan Niu
- Department of Nephrology, Henan Provincial Key Laboratory of Kidney Disease and Immunology, Henan Provincial People's Hospital (Zhengzhou University People's Hospital), Zhengzhou, China
| | - Fengmin Shao
- Department of Nephrology, Henan Provincial Key Laboratory of Kidney Disease and Immunology, Henan Provincial People's Hospital (Zhengzhou University People's Hospital), Zhengzhou, China
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10
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Poveda J, Vázquez-Sánchez S, Sanz AB, Ortiz A, Ruilope LM, Ruiz-Hurtado G. TWEAK-Fn14 as a common pathway in the heart and the kidneys in cardiorenal syndrome. J Pathol 2021; 254:5-19. [PMID: 33512736 DOI: 10.1002/path.5631] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 12/23/2020] [Accepted: 01/12/2021] [Indexed: 12/19/2022]
Abstract
There is a complex relationship between cardiac and renal disease, often referred to as the cardiorenal syndrome. Heart failure adversely affects kidney function, and both acute and chronic kidney disease are associated with structural and functional changes to the myocardium. The pathological mechanisms and contributing interactions that surround this relationship remain poorly understood, limiting the opportunities for therapeutic intervention. The cytokine tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor, fibroblast growth factor-inducible 14 (Fn14), are abundantly expressed in injured kidneys and heart. The TWEAK-Fn14 axis promotes responses that drive tissue injury such as inflammation, proliferation, fibrosis, and apoptosis, while restraining the expression of tissue protective factors such as the anti-aging factor Klotho and the master regulator of mitochondrial biogenesis peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). High levels of TWEAK induce cardiac remodeling, and promote inflammation, tubular and podocyte injury and death, fibroblast proliferation, and, ultimately, renal fibrosis. Accordingly, targeting the TWEAK-Fn14 axis is protective in experimental kidney and heart disease. TWEAK has also emerged as a biomarker of kidney damage and cardiovascular outcomes and has been successfully targeted in clinical trials. In this review, we update our current knowledge of the roles of the TWEAK-Fn14 axis in cardiovascular and kidney disease and its potential contribution to the cardiorenal syndrome. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Jonay Poveda
- Cardiorenal Translational Laboratory, Institute of Research i+12, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Sara Vázquez-Sánchez
- Cardiorenal Translational Laboratory, Institute of Research i+12, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Ana B Sanz
- Research Institute - Fundacion Jimenez Diaz, Autonoma University, Madrid, Spain.,REDINREN, Madrid, Spain
| | - Alberto Ortiz
- Research Institute - Fundacion Jimenez Diaz, Autonoma University, Madrid, Spain.,REDINREN, Madrid, Spain
| | - Luis M Ruilope
- Cardiorenal Translational Laboratory, Institute of Research i+12, Hospital Universitario 12 de Octubre, Madrid, Spain.,School of Doctoral Studies and Research, European University of Madrid, Madrid, Spain.,CIBER-CV, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Gema Ruiz-Hurtado
- Cardiorenal Translational Laboratory, Institute of Research i+12, Hospital Universitario 12 de Octubre, Madrid, Spain.,CIBER-CV, Hospital Universitario 12 de Octubre, Madrid, Spain
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11
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Carriazo S, Ramos AM, Sanz AB, Sanchez-Niño MD, Kanbay M, Ortiz A. Chronodisruption: A Poorly Recognized Feature of CKD. Toxins (Basel) 2020; 12:E151. [PMID: 32121234 PMCID: PMC7150823 DOI: 10.3390/toxins12030151] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 02/17/2020] [Accepted: 02/20/2020] [Indexed: 02/07/2023] Open
Abstract
Multiple physiological variables change over time in a predictable and repetitive manner, guided by molecular clocks that respond to external and internal clues and are coordinated by a central clock. The kidney is the site of one of the most active peripheral clocks. Biological rhythms, of which the best known are circadian rhythms, are required for normal physiology of the kidneys and other organs. Chronodisruption refers to the chronic disruption of circadian rhythms leading to disease. While there is evidence that circadian rhythms may be altered in kidney disease and that altered circadian rhythms may accelerate chronic kidney disease (CKD) progression, there is no comprehensive review on chronodisruption and chronodisruptors in CKD and its manifestations. Indeed, the term chronodisruption has been rarely applied to CKD despite chronodisruptors being potential therapeutic targets in CKD patients. We now discuss evidence for chronodisruption in CKD and the impact of chronodisruption on CKD manifestations, identify potential chronodisruptors, some of them uremic toxins, and their therapeutic implications, and discuss current unanswered questions on this topic.
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Affiliation(s)
- Sol Carriazo
- IIS-Fundacion Jimenez Diaz, Department of Medicine, Universidad Autonoma de Madrid, Fundacion Renal Iñigo Alvarez de Toledo-IRSIN, 28040 Madrid, Spain; (S.C.); (A.MR.); (A.BS.); (M.D.S.-N.)
- Red de Investigación Renal (REDINREN), 28040 Madrid, Spain
| | - Adrián M Ramos
- IIS-Fundacion Jimenez Diaz, Department of Medicine, Universidad Autonoma de Madrid, Fundacion Renal Iñigo Alvarez de Toledo-IRSIN, 28040 Madrid, Spain; (S.C.); (A.MR.); (A.BS.); (M.D.S.-N.)
- Red de Investigación Renal (REDINREN), 28040 Madrid, Spain
| | - Ana B Sanz
- IIS-Fundacion Jimenez Diaz, Department of Medicine, Universidad Autonoma de Madrid, Fundacion Renal Iñigo Alvarez de Toledo-IRSIN, 28040 Madrid, Spain; (S.C.); (A.MR.); (A.BS.); (M.D.S.-N.)
- Red de Investigación Renal (REDINREN), 28040 Madrid, Spain
| | - Maria Dolores Sanchez-Niño
- IIS-Fundacion Jimenez Diaz, Department of Medicine, Universidad Autonoma de Madrid, Fundacion Renal Iñigo Alvarez de Toledo-IRSIN, 28040 Madrid, Spain; (S.C.); (A.MR.); (A.BS.); (M.D.S.-N.)
- Red de Investigación Renal (REDINREN), 28040 Madrid, Spain
| | - Mehmet Kanbay
- Division of Nephrology, Department of Medicine, Koc University School of Medicine, 34010 Istanbul, Turkey;
| | - Alberto Ortiz
- IIS-Fundacion Jimenez Diaz, Department of Medicine, Universidad Autonoma de Madrid, Fundacion Renal Iñigo Alvarez de Toledo-IRSIN, 28040 Madrid, Spain; (S.C.); (A.MR.); (A.BS.); (M.D.S.-N.)
- Red de Investigación Renal (REDINREN), 28040 Madrid, Spain
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12
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TRAIL, OPG, and TWEAK in kidney disease: biomarkers or therapeutic targets? Clin Sci (Lond) 2019; 133:1145-1166. [PMID: 31097613 PMCID: PMC6526163 DOI: 10.1042/cs20181116] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2018] [Revised: 04/19/2019] [Accepted: 04/29/2019] [Indexed: 12/11/2022]
Abstract
Ligands and receptors of the tumor necrosis factor (TNF) superfamily regulate immune responses and homeostatic functions with potential diagnostic and therapeutic implications. Kidney disease represents a global public health problem, whose prevalence is rising worldwide, due to the aging of the population and the increasing prevalence of diabetes, hypertension, obesity, and immune disorders. In addition, chronic kidney disease is an independent risk factor for the development of cardiovascular disease, which further increases kidney-related morbidity and mortality. Recently, it has been shown that some TNF superfamily members are actively implicated in renal pathophysiology. These members include TNF-related apoptosis-inducing ligand (TRAIL), its decoy receptor osteoprotegerin (OPG), and TNF-like weaker inducer of apoptosis (TWEAK). All of them have shown the ability to activate crucial pathways involved in kidney disease development and progression (e.g. canonical and non-canonical pathways of the transcription factor nuclear factor-kappa B), as well as the ability to regulate cell proliferation, differentiation, apoptosis, necrosis, inflammation, angiogenesis, and fibrosis with double-edged effects depending on the type and stage of kidney injury. Here we will review the actions of TRAIL, OPG, and TWEAK on diabetic and non-diabetic kidney disease, in order to provide insights into their full clinical potential as biomarkers and/or therapeutic options against kidney disease.
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13
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Valiño-Rivas L, Vaquero JJ, Sucunza D, Gutierrez S, Sanz AB, Fresno M, Ortiz A, Sanchez-Niño MD. NIK as a Druggable Mediator of Tissue Injury. Trends Mol Med 2019; 25:341-360. [PMID: 30926358 DOI: 10.1016/j.molmed.2019.02.005] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Revised: 02/07/2019] [Accepted: 02/13/2019] [Indexed: 12/15/2022]
Abstract
NF-κB-inducing kinase (NIK, MAP3K14) is best known as the apical kinase that triggers non-canonical NF-κB activation and by its role in the immune system. Recent data indicate a role for NIK expressed by non-lymphoid cells in cancer, kidney disease, liver injury, glucose homeostasis, osteosarcopenia, vascular calcification, hematopoiesis, and endothelial function. The spectrum of NIK-associated disease now ranges from immunodeficiency (when NIK is defective) to autoimmunity, cancer, sterile inflammation, fibrosis, and metabolic disease when NIK is overactive. The development of novel small-molecule NIK inhibitors has paved the way to test NIK targeting to treat disease in vivo, and may eventually lead to NIK targeting in the clinic. In addition, NIK activators are being explored for specific conditions such as myeloid leukemia.
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Affiliation(s)
- Lara Valiño-Rivas
- Department of Nephrology and Hypertension, Instituto de Investigación Sanitaria (IIS) Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid (UAM), Red de Investigación Renal (REDINREN), and Fundación Renal Íñigo Álvarez de Toledo (FRIAT), Madrid, Spain
| | - Juan José Vaquero
- Departamento de Química Orgánica y Química Inorgánica, Universidad de Alcala and REDINREN, Madrid, Spain
| | - David Sucunza
- Departamento de Química Orgánica y Química Inorgánica, Universidad de Alcala and REDINREN, Madrid, Spain
| | - Sara Gutierrez
- Departamento de Química Orgánica y Química Inorgánica, Universidad de Alcala and REDINREN, Madrid, Spain
| | - Ana B Sanz
- Department of Nephrology and Hypertension, Instituto de Investigación Sanitaria (IIS) Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid (UAM), Red de Investigación Renal (REDINREN), and Fundación Renal Íñigo Álvarez de Toledo (FRIAT), Madrid, Spain
| | - Manuel Fresno
- Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas de la UAM, Madrid, Spain
| | - Alberto Ortiz
- Department of Nephrology and Hypertension, Instituto de Investigación Sanitaria (IIS) Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid (UAM), Red de Investigación Renal (REDINREN), and Fundación Renal Íñigo Álvarez de Toledo (FRIAT), Madrid, Spain; These authors contributed equally.
| | - Maria Dolores Sanchez-Niño
- Department of Nephrology and Hypertension, Instituto de Investigación Sanitaria (IIS) Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid (UAM), Red de Investigación Renal (REDINREN), and Fundación Renal Íñigo Álvarez de Toledo (FRIAT), Madrid, Spain; These authors contributed equally.
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14
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Kandemir FM, Yildirim S, Kucukler S, Caglayan C, Mahamadu A, Dortbudak MB. Therapeutic efficacy of zingerone against vancomycin-induced oxidative stress, inflammation, apoptosis and aquaporin 1 permeability in rat kidney. Biomed Pharmacother 2018; 105:981-991. [DOI: 10.1016/j.biopha.2018.06.048] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Revised: 06/12/2018] [Accepted: 06/12/2018] [Indexed: 01/01/2023] Open
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15
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Restorative potentiality of S-allylcysteine against diabetic nephropathy through attenuation of oxidative stress and inflammation in streptozotocin-nicotinamide-induced diabetic rats. Eur J Nutr 2018; 58:2425-2437. [PMID: 30062492 DOI: 10.1007/s00394-018-1795-x] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Accepted: 07/24/2018] [Indexed: 12/24/2022]
Abstract
AIM In the present study, we evaluated the therapeutic potentiality of S-allylcysteine (SAC) in streptozotocin (STZ)-nicotinamide (NAD)-induced diabetic nephropathy (DN) in experimental rats. METHODS SAC was orally administered for 45 days to rats with STZ-NAD-induced DN; a metformin-treated group was included for comparison. Effect of SAC on body weight, organ weight, blood glucose, levels of insulin, glycated haemoglobin, and renal biochemical markers was determined. Body composition by total body electrical conductivity (TOBEC) and dual-X ray absorptiometry (DXA), kidney antioxidant analysis, real-time polymerase chain reaction, and western blot analysis of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), nuclear factor kappa B (NF-κB), interleukin (IL)-6, and tumor necrosis factor (TNF)-α; histopathological and scanning electron microscope (SEM) analysis of the kidneys were performed in both control and experimental rats. RESULTS SAC treatment showed significantly decreased levels of blood glucose, glycated haemoglobin, creatinine, albumin, AST, ALT, creatinine kinase, lactate dehydrogenase, and expressions of NF-κB, IL-6, and TNF-α compared with DN control rats. Furthermore, SAC administration to DN rats significantly improved body composition and antioxidant defense mechanism which was confirmed by the upregulation of mRNA and protein expressions of antioxidant genes. CONCLUSIONS Thus, SAC showed adequate therapeutic effect against DN by downregulation of inflammatory factors and attenuation of oxidative stress. Histological and SEM observations also indicated that SAC treatment notably reverses renal damage and protects the kidneys from hyperglycemia-mediated oxidative damage.
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16
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Cellular and molecular mechanisms of kidney fibrosis. Mol Aspects Med 2018; 65:16-36. [PMID: 29909119 DOI: 10.1016/j.mam.2018.06.002] [Citation(s) in RCA: 310] [Impact Index Per Article: 44.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Accepted: 06/12/2018] [Indexed: 12/14/2022]
Abstract
Renal fibrosis is the final pathological process common to any ongoing, chronic kidney injury or maladaptive repair. It is considered as the underlying pathological process of chronic kidney disease (CKD), which affects more than 10% of world population and for which treatment options are limited. Renal fibrosis is defined by excessive deposition of extracellular matrix, which disrupts and replaces the functional parenchyma that leads to organ failure. Kidney's histological structure can be divided into three main compartments, all of which can be affected by fibrosis, specifically termed glomerulosclerosis in glomeruli, interstitial fibrosis in tubulointerstitium and arteriosclerosis and perivascular fibrosis in vasculature. In this review, we summarized the different appearance, cellular origin and major emerging processes and mediators of fibrosis in each compartment. We also depicted and discussed the challenges in translation of anti-fibrotic treatment to clinical practice and discuss possible solutions and future directions.
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17
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Gremlin activates the Notch pathway linked to renal inflammation. Clin Sci (Lond) 2018; 132:1097-1115. [PMID: 29720422 DOI: 10.1042/cs20171553] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 04/27/2018] [Accepted: 05/02/2018] [Indexed: 02/07/2023]
Abstract
Preclinical studies suggest that Gremlin participates in renal damage and could be a potential therapeutic target for human chronic kidney diseases. Inflammation is a common characteristic of progressive renal disease, and therefore novel anti-inflammatory therapeutic targets should be investigated. The Notch signaling pathway is involved in kidney development and is activated in human chronic kidney disease, but whether Gremlin regulates the Notch pathway has not been investigated. In cultured tubular cells, Gremlin up-regulated gene expression of several Notch pathway components, increased the production of the canonical ligand Jagged-1, and caused the nuclear translocation of active Notch-1 (N1ICD). In vivo administration of Gremlin into murine kidneys elicited Jagged-1 production, increased N1ICD nuclear levels, and up-regulated the gene expression of the Notch effectors hes-1 and hey-1 All these data clearly demonstrate that Gremlin activates the Notch pathway in the kidney. Notch inhibition using the γ-secretase inhibitor DAPT impaired renal inflammatory cell infiltration and proinflammatory cytokines overexpression in Gremlin-injected mice and in experimental models of renal injury. Moreover, Notch inhibition blocked Gremlin-induced activation of the canonical and noncanonical nuclear factor-κB (NF-κB) pathway, identifying an important mechanism involved in the anti-inflammatory actions of Notch inhibition. In conclusion, Gremlin activates the Notch pathway in the kidney and this is linked to NF-κB-mediated inflammation, supporting the hypothesis that Notch inhibition could be a potential anti-inflammatory strategy for renal diseases.
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18
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Assessment of urinary TWEAK levels in Mexican patients with untreated lupus nephritis: An exploratory study. Nefrologia 2018; 38:152-160. [DOI: 10.1016/j.nefro.2017.04.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Revised: 04/22/2017] [Accepted: 04/28/2017] [Indexed: 11/24/2022] Open
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19
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Blockade of histone deacetylase 6 protects against cisplatin-induced acute kidney injury. Clin Sci (Lond) 2018; 132:339-359. [PMID: 29358506 DOI: 10.1042/cs20171417] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Revised: 01/04/2018] [Accepted: 01/22/2018] [Indexed: 12/21/2022]
Abstract
Histone deacetylase 6 (HDAC6) has been shown to be involved in various pathological conditions, including cancer, neurodegenerative disorders and inflammatory diseases. Nonetheless, its specific role in drug-induced nephrotoxicity is poorly understood. Cisplatin (dichlorodiamino platinum) belongs to an inorganic platinum - fundamental chemotherapeutic drug utilized in the therapy of various solid malignant tumors. However, the use of cisplatin is extremely limited by obvious side effects, for instance bone marrow suppression and nephrotoxicity. In the present study, we utilized a murine model of cisplatin-induced acute kidney injury (AKI) and a highly selective inhibitor of HDAC6, tubastatin A (TA), to assess the role of HDAC6 in nephrotoxicity and its associated mechanisms. Cisplatin-induced AKI was accompanied by increased expression and activation of HDAC6; blocking HDAC6 with TA lessened renal dysfunction, attenuated renal pathological changes, reduced expression of neutrophil gelatinase-associated lipocalin and kidney injury molecule 1, and decreased tubular cell apoptosis. In cultured human epithelial cells, TA or HDAC6 siRNA treatment also inhibited cisplatin-induced apoptosis. Mechanistic studies demonstrated that cisplatin treatment induced phosphorylation of AKT and loss of E-cadherin in the nephrotoxic kidney, and administration of TA enhanced AKT phosphorylation and preserved E-cadherin expression. HDAC6 inhibition also potentiated autophagy as evidenced by increased expression of autophagy-related gene (Atg) 7 (Atg7), Beclin-1, and decreased renal oxidative stress as demonstrated by up-regulation of superoxide dismutase (SOD) activity and down-regulation of malondialdehyde levels. Moreover, TA was effective in inhibiting nuclear factor-κ B (NF-κB) phosphorylation and suppressing the expression of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Collectively, these data provide strong evidence that HDAC6 inhibition is protective against cisplatin-induced AKI and suggest that HDAC6 may be a potential therapeutic target for AKI treatment.
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20
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Brightbill HD, Suto E, Blaquiere N, Ramamoorthi N, Sujatha-Bhaskar S, Gogol EB, Castanedo GM, Jackson BT, Kwon YC, Haller S, Lesch J, Bents K, Everett C, Kohli PB, Linge S, Christian L, Barrett K, Jaochico A, Berezhkovskiy LM, Fan PW, Modrusan Z, Veliz K, Townsend MJ, DeVoss J, Johnson AR, Godemann R, Lee WP, Austin CD, McKenzie BS, Hackney JA, Crawford JJ, Staben ST, Alaoui Ismaili MH, Wu LC, Ghilardi N. NF-κB inducing kinase is a therapeutic target for systemic lupus erythematosus. Nat Commun 2018; 9:179. [PMID: 29330524 PMCID: PMC5766581 DOI: 10.1038/s41467-017-02672-0] [Citation(s) in RCA: 93] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Accepted: 12/18/2017] [Indexed: 02/06/2023] Open
Abstract
NF-κB-inducing kinase (NIK) mediates non-canonical NF-κB signaling downstream of multiple TNF family members, including BAFF, TWEAK, CD40, and OX40, which are implicated in the pathogenesis of systemic lupus erythematosus (SLE). Here, we show that experimental lupus in NZB/W F1 mice can be treated with a highly selective and potent NIK small molecule inhibitor. Both in vitro as well as in vivo, NIK inhibition recapitulates the pharmacological effects of BAFF blockade, which is clinically efficacious in SLE. Furthermore, NIK inhibition also affects T cell parameters in the spleen and proinflammatory gene expression in the kidney, which may be attributable to inhibition of OX40 and TWEAK signaling, respectively. As a consequence, NIK inhibition results in improved survival, reduced renal pathology, and lower proteinuria scores. Collectively, our data suggest that NIK inhibition is a potential therapeutic approach for SLE.
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Affiliation(s)
- Hans D Brightbill
- Department of Immunology Discovery, Genentech, 1 DNA Way, South San Francisco, CA-94080, USA
| | - Eric Suto
- Department of Translational Immunology, Genentech, 1 DNA Way, South San Francisco, CA-94080, USA
| | - Nicole Blaquiere
- Department of Discovery Chemistry, Genentech, 1 DNA Way, South San Francisco, CA-94080, USA
| | - Nandhini Ramamoorthi
- Department of Biomarker Discovery, Genentech, 1 DNA Way, South San Francisco, CA-94080, USA
| | - Swathi Sujatha-Bhaskar
- Department of Immunology Discovery, Genentech, 1 DNA Way, South San Francisco, CA-94080, USA
| | - Emily B Gogol
- Department of Immunology Discovery, Genentech, 1 DNA Way, South San Francisco, CA-94080, USA
| | - Georgette M Castanedo
- Department of Discovery Chemistry, Genentech, 1 DNA Way, South San Francisco, CA-94080, USA
| | - Benjamin T Jackson
- Department of Immunology Discovery, Genentech, 1 DNA Way, South San Francisco, CA-94080, USA
| | - Youngsu C Kwon
- Department of Translational Immunology, Genentech, 1 DNA Way, South San Francisco, CA-94080, USA
| | - Susan Haller
- Department of Pathology, Genentech, 1 DNA Way, South San Francisco, CA-94080, USA
| | - Justin Lesch
- Department of Translational Immunology, Genentech, 1 DNA Way, South San Francisco, CA-94080, USA
| | - Karin Bents
- Evotec, Inc., Essener Bogen 7, Hamburg, 22419, Germany
| | - Christine Everett
- Department of Biochemical and Cellular Pharmacology, Genentech, 1 DNA Way, South San Francisco, CA-94080, USA
| | - Pawan Bir Kohli
- Department of Biochemical and Cellular Pharmacology, Genentech, 1 DNA Way, South San Francisco, CA-94080, USA
| | - Sandra Linge
- Evotec, Inc., Essener Bogen 7, Hamburg, 22419, Germany
| | - Laura Christian
- Department of Immunology Discovery, Genentech, 1 DNA Way, South San Francisco, CA-94080, USA
| | - Kathy Barrett
- Department of Biochemical and Cellular Pharmacology, Genentech, 1 DNA Way, South San Francisco, CA-94080, USA
| | - Allan Jaochico
- Department of Drug Metabolism and Pharmacokinetics, Genentech, 1 DNA Way, South San Francisco, CA-94080, USA
| | - Leonid M Berezhkovskiy
- Department of Drug Metabolism and Pharmacokinetics, Genentech, 1 DNA Way, South San Francisco, CA-94080, USA
| | - Peter W Fan
- Department of Drug Metabolism and Pharmacokinetics, Genentech, 1 DNA Way, South San Francisco, CA-94080, USA
| | - Zora Modrusan
- Department of Molecular Biology, Genentech, 1 DNA Way, South San Francisco, CA-94080, USA
| | - Kelli Veliz
- Department of Laboratory Animal Resources, Genentech, 1 DNA Way, South San Francisco, CA-94080, USA
| | - Michael J Townsend
- Department of Biomarker Discovery, Genentech, 1 DNA Way, South San Francisco, CA-94080, USA
| | - Jason DeVoss
- Department of Translational Immunology, Genentech, 1 DNA Way, South San Francisco, CA-94080, USA
| | - Adam R Johnson
- Department of Biochemical and Cellular Pharmacology, Genentech, 1 DNA Way, South San Francisco, CA-94080, USA
| | | | - Wyne P Lee
- Department of Translational Immunology, Genentech, 1 DNA Way, South San Francisco, CA-94080, USA
| | - Cary D Austin
- Department of Pathology, Genentech, 1 DNA Way, South San Francisco, CA-94080, USA
| | - Brent S McKenzie
- Department of Translational Immunology, Genentech, 1 DNA Way, South San Francisco, CA-94080, USA
| | - Jason A Hackney
- Department of Bioinformatics and Computational Biology, Genentech, 1 DNA Way, South San Francisco, CA-94080, USA
| | - James J Crawford
- Department of Discovery Chemistry, Genentech, 1 DNA Way, South San Francisco, CA-94080, USA
| | - Steven T Staben
- Department of Discovery Chemistry, Genentech, 1 DNA Way, South San Francisco, CA-94080, USA
| | - Moulay H Alaoui Ismaili
- Department of Biochemical and Cellular Pharmacology, Genentech, 1 DNA Way, South San Francisco, CA-94080, USA
| | - Lawren C Wu
- Department of Immunology Discovery, Genentech, 1 DNA Way, South San Francisco, CA-94080, USA
| | - Nico Ghilardi
- Department of Immunology Discovery, Genentech, 1 DNA Way, South San Francisco, CA-94080, USA.
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21
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Guo Y, Liao Y. miR-200bc/429 cluster alleviates inflammation in IgA nephropathy by targeting TWEAK/Fn14. Int Immunopharmacol 2017; 52:150-155. [PMID: 28910745 DOI: 10.1016/j.intimp.2017.09.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Revised: 08/27/2017] [Accepted: 09/05/2017] [Indexed: 12/21/2022]
Abstract
Immunoglobulin A nephropathy (IgAN) is one of the most common glomerular diseases worldwide. Various studies have identified a host of microRNAs (miRNAs) abnormally expressed in IgAN and might affect the pathogenesis and progression of IgAN. However, miR-200bc/429 cluster in the pathopoiesis of IgAN remains poorly understood. For this study, we found that miR-200bc/429 cluster is downregulated in IgAN tissues and IgAN podocytes and HK2 cells compared with their matched controls respectively. In addition, overexpression of miR-200bc/429 cluster in IgAN podocytes and HK2 cells could attenuate the release of inflammatory cytokines MCP-1, IL-6 and RANTES. Moreover, the 3' untranslated region (UTR) of TNF-like weak inducer of apoptosis (TWEAK) was identified to be a direct target of miR-200bc/429 cluster. Furthermore, our results showed that miR-200bc/429 cluster can inhibit TWEAK mediated NF-κB pathway activation in IgAN. Overall, our findings revealed that miR-200bc/429 cluster alleviates inflammation in IgAN through TWEAK/Fn14 system and might serve as a biomarker as well as a promising therapeutic target for IgAN.
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Affiliation(s)
- Yong Guo
- Department of Nephrology, Chongqing Ninth People's Hospital, Chongqing 400700, People's Republic of China
| | - Yuanjiang Liao
- Department of Nephrology, Chongqing Ninth People's Hospital, Chongqing 400700, People's Republic of China.
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22
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Martin-Lorenzo M, Gonzalez-Calero L, Ramos-Barron A, Sanchez-Niño MD, Gomez-Alamillo C, García-Segura JM, Ortiz A, Arias M, Vivanco F, Alvarez-Llamas G. Urine metabolomics insight into acute kidney injury point to oxidative stress disruptions in energy generation and H 2S availability. J Mol Med (Berl) 2017; 95:1399-1409. [PMID: 28975359 DOI: 10.1007/s00109-017-1594-5] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Revised: 08/03/2017] [Accepted: 09/12/2017] [Indexed: 11/26/2022]
Abstract
Acute kidney injury (AKI) is one of the main complications in acute care medicine and a risk factor for chronic kidney disease (CKD). AKI incidence has increased; however, its diagnosis has limitations and physiopathological mechanisms are underexplored. We investigated urine samples, aiming to identify major metabolite changes during human AKI evolution. Metabolic signatures found were further explored for a potential link to severity of injury. Twenty-four control subjects and 38 hospitalized patients with AKI were recruited and urine samples were collected at the time of diagnosis, during follow-up and at discharge. Nuclear magnetic resonance (NMR) was used in a first discovery phase for identifying potential metabolic differences. Target metabolites of interest were confirmed by liquid chromatography-mass spectrometry (LC-MS/MS) in an independent group. Underlying metabolic defects were further explored by kidney transcriptomics of murine toxic AKI. Urinary 2-hydroxybutyric acid, pantothenic acid, and hippuric acid were significantly downregulated and urinary N-acetylneuraminic acid, phosphoethanolamine, and serine were upregulated during AKI. Hippuric acid, phosphoethanolamine, and serine showed further downregulation/upregulation depending on the metabolite in acute tubular necrosis (ATN) AKI compared to prerenal AKI. Kidney transcriptomics disclosed decreased expression of cystathionase, cystathionine-β-synthase, and ethanolamine-phosphate cytidylyltransferase, and increased N-acetylneuraminate synthase as the potentially underlying cause of changes in urinary metabolites. A urinary metabolite panel identified AKI patients and provided insight into intrarenal events. A urine fingerprint made up of six metabolites may be related to pathophysiological changes in oxidative stress, energy generation, and H2S availability associated with AKI. KEY MESSAGES The urinary metabolome reflects AKI evolution and severity of injury. Kidney transcriptomics revealed enzymatic expression changes. Enzymatic expression changes may be the potentially underlying cause of changes in urine metabolites. Identified metabolite changes link oxidative stress, energy generation, and H2S availability to AKI.
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Affiliation(s)
- Marta Martin-Lorenzo
- Department of Immunology, IIS-Fundacion Jimenez Diaz-UAM, REDinREN, Madrid, Spain
| | | | - Angeles Ramos-Barron
- Nephrology Department, Hospital Valdecilla, Universidad de Cantabria, Instituto de Investigación Marqués de Valdecilla, IDIVAL, Santander, Cantabria, Spain
| | - Maria D Sanchez-Niño
- Department of Nephrology/IRSIN, IIS-Fundación Jiménez Díaz-UAM, REDinREN, Madrid, Spain
| | - Carlos Gomez-Alamillo
- Nephrology Department, Hospital Valdecilla, Universidad de Cantabria, Instituto de Investigación Marqués de Valdecilla, IDIVAL, Santander, Cantabria, Spain
| | - Juan Manuel García-Segura
- CAI-RMN, Universidad Complutense, Madrid, Spain
- Department of Biochemistry and Molecular Biology I, Universidad Complutense, Madrid, Spain
| | - Alberto Ortiz
- Department of Nephrology/IRSIN, IIS-Fundación Jiménez Díaz-UAM, REDinREN, Madrid, Spain
| | - Manuel Arias
- Nephrology Department, Hospital Valdecilla, Universidad de Cantabria, Instituto de Investigación Marqués de Valdecilla, IDIVAL, Santander, Cantabria, Spain
| | - Fernando Vivanco
- Department of Immunology, IIS-Fundacion Jimenez Diaz-UAM, REDinREN, Madrid, Spain
- Department of Biochemistry and Molecular Biology I, Universidad Complutense, Madrid, Spain
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23
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The non-canonical NF-κB pathway in immunity and inflammation. NATURE REVIEWS. IMMUNOLOGY 2017. [PMID: 28580957 DOI: 10.1038/nri.2017.52)] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
The nuclear factor-κB (NF-κB) family of transcription factors is activated by canonical and non-canonical signalling pathways, which differ in both signalling components and biological functions. Recent studies have revealed important roles for the non-canonical NF-κB pathway in regulating different aspects of immune functions. Defects in non-canonical NF-κB signalling are associated with severe immune deficiencies, whereas dysregulated activation of this pathway contributes to the pathogenesis of various autoimmune and inflammatory diseases. Here we review the signalling mechanisms and the biological function of the non-canonical NF-κB pathway. We also discuss recent progress in elucidating the molecular mechanisms regulating non-canonical NF-κB pathway activation, which may provide new opportunities for therapeutic strategies.
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24
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Poveda J, Sanz AB, Carrasco S, Ruiz-Ortega M, Cannata-Ortiz P, Sanchez-Niño MD, Ortiz A. Bcl3: a regulator of NF-κB inducible by TWEAK in acute kidney injury with anti-inflammatory and antiapoptotic properties in tubular cells. Exp Mol Med 2017; 49:e352. [PMID: 28684863 PMCID: PMC5565957 DOI: 10.1038/emm.2017.89] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Revised: 12/21/2016] [Accepted: 01/12/2017] [Indexed: 01/09/2023] Open
Abstract
Acute kidney injury (AKI) is characterized by tubular cell death and interstitial inflammation. TWEAK promotes experimental kidney injury and activates the transcription factor NF-κB, a key regulator of genes involved in cell survival and inflammatory response. In search of potential therapeutic targets for AKI, we compared a transcriptomics database of NF-κB-related genes from murine AKI-kidneys with a transcriptomics database of TWEAK-stimulated cultured tubular cells. Four out of twenty-four (17%) genes were significantly upregulated (false discovery rate, FDR<0.05), while nine out of twenty-four (37%) genes were significantly upregulated at FDR <0.1 in both databases. Bcl3 was the top upregulated NF-κB-related gene in experimental AKI and one of the most upregulated genes in TWEAK-stimulated tubular cells. Quantitative reverse transcription PCR (qRT-PCR), western blot and immunohistochemistry confirmed Bcl3 upregulation in both experimental conditions and localized increased Bcl3 expression to tubular cells in AKI. Transcriptomics database analysis revealed increased Bcl3 expression in numerous experimental and human kidney conditions. Furthermore, systemic TWEAK administration increased kidney Bcl3 expression. In cultured tubular cells, targeting Bcl3 by siRNA resulted in the magnification of TWEAK-induced NF-κB transcriptional activity, chemokine upregulation and Klotho downregulation, and in the sensitization to cell death induced by TWEAK/TNFα/interferon-γ. In contrast, Bcl3 overexpression decreased NF-κB transcriptional activity, inflammatory response and cell death while dampening the decrease in Klotho expression. In conclusion, Bcl3 expressed in response to TWEAK stimulation decreases TWEAK-induced inflammatory and lethal responses. Therefore, therapeutic upregulation of Bcl3 activity should be explored in kidney disease because it has advantages over chemical inhibitors of NF-κB that are known to prevent inflammatory responses but can also sensitize the cells to apoptosis.
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Affiliation(s)
- Jonay Poveda
- Unidad de Dialisis, IIS-Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid, Fundación Renal Iñigo Álvarez de Toledo-IRSIN and REDINREN, Madrid, Spain
| | - Ana B Sanz
- Unidad de Dialisis, IIS-Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid, Fundación Renal Iñigo Álvarez de Toledo-IRSIN and REDINREN, Madrid, Spain
| | - Susana Carrasco
- Unidad de Dialisis, IIS-Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid, Fundación Renal Iñigo Álvarez de Toledo-IRSIN and REDINREN, Madrid, Spain
| | - Marta Ruiz-Ortega
- Unidad de Dialisis, IIS-Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid, Fundación Renal Iñigo Álvarez de Toledo-IRSIN and REDINREN, Madrid, Spain
| | - Pablo Cannata-Ortiz
- Unidad de Dialisis, IIS-Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid, Fundación Renal Iñigo Álvarez de Toledo-IRSIN and REDINREN, Madrid, Spain
| | - Maria D Sanchez-Niño
- Unidad de Dialisis, IIS-Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid, Fundación Renal Iñigo Álvarez de Toledo-IRSIN and REDINREN, Madrid, Spain
| | - Alberto Ortiz
- Unidad de Dialisis, IIS-Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid, Fundación Renal Iñigo Álvarez de Toledo-IRSIN and REDINREN, Madrid, Spain
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25
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Abstract
The nuclear factor-κB (NF-κB) family of transcription factors is activated by canonical and non-canonical signalling pathways, which differ in both signalling components and biological functions. Recent studies have revealed important roles for the non-canonical NF-κB pathway in regulating different aspects of immune functions. Defects in non-canonical NF-κB signalling are associated with severe immune deficiencies, whereas dysregulated activation of this pathway contributes to the pathogenesis of various autoimmune and inflammatory diseases. Here we review the signalling mechanisms and the biological function of the non-canonical NF-κB pathway. We also discuss recent progress in elucidating the molecular mechanisms regulating non-canonical NF-κB pathway activation, which may provide new opportunities for therapeutic strategies.
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Affiliation(s)
- Shao-Cong Sun
- Department of Immunology, The University of Texas MD Anderson Cancer Center, MD Anderson Cancer Center UT Heath Graduate School of Biomedical Sciences, 7455 Fannin Street, Box 902, Houston, Texas 77030, USA
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26
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Martin-Sanchez D, Gallegos-Villalobos A, Fontecha-Barriuso M, Carrasco S, Sanchez-Niño MD, Lopez-Hernandez FJ, Ruiz-Ortega M, Egido J, Ortiz A, Sanz AB. Deferasirox-induced iron depletion promotes BclxL downregulation and death of proximal tubular cells. Sci Rep 2017; 7:41510. [PMID: 28139717 PMCID: PMC5282523 DOI: 10.1038/srep41510] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Accepted: 12/21/2016] [Indexed: 12/21/2022] Open
Abstract
Iron deficiency has been associated with kidney injury. Deferasirox is an oral iron chelator used to treat blood transfusion-related iron overload. Nephrotoxicity is the most serious and common adverse effect of deferasirox and may present as an acute or chronic kidney disease. However, scarce data are available on the molecular mechanisms of nephrotoxicity. We explored the therapeutic modulation of deferasirox-induced proximal tubular cell death in culture. Deferasirox induced dose-dependent tubular cell death and AnexxinV/7AAD staining showed features of apoptosis and necrosis. However, despite inhibiting caspase-3 activation, the pan-caspase inhibitor zVAD-fmk failed to prevent deferasirox-induced cell death. Moreover, zVAD increased deferasirox-induced cell death, a feature sometimes found in necroptosis. Electron microscopy identified mitochondrial injury and features of necrosis. However, neither necrostatin-1 nor RIP3 knockdown prevented deferasirox-induced cell death. Deferasirox caused BclxL depletion and BclxL overexpression was protective. Preventing iron depletion protected from BclxL downregulation and deferasirox cytotoxicity. In conclusion, deferasirox promoted iron depletion-dependent cell death characterized by BclxL downregulation. BclxL overexpression was protective, suggesting a role for BclxL downregulation in iron depletion-induced cell death. This information may be used to develop novel nephroprotective strategies. Furthermore, it supports the concept that monitoring kidney tissue iron depletion may decrease the risk of deferasirox nephrotoxicity.
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Affiliation(s)
- Diego Martin-Sanchez
- Research Institute-Fundacion Jimenez Diaz, Autonoma University, Madrid, Spain
- IRSIN, Madrid, Spain
- REDINREN, Madrid, Spain
| | - Angel Gallegos-Villalobos
- Research Institute-Fundacion Jimenez Diaz, Autonoma University, Madrid, Spain
- IRSIN, Madrid, Spain
- REDINREN, Madrid, Spain
| | - Miguel Fontecha-Barriuso
- Research Institute-Fundacion Jimenez Diaz, Autonoma University, Madrid, Spain
- IRSIN, Madrid, Spain
- REDINREN, Madrid, Spain
| | - Susana Carrasco
- Research Institute-Fundacion Jimenez Diaz, Autonoma University, Madrid, Spain
- IRSIN, Madrid, Spain
- REDINREN, Madrid, Spain
| | - Maria Dolores Sanchez-Niño
- Research Institute-Fundacion Jimenez Diaz, Autonoma University, Madrid, Spain
- IRSIN, Madrid, Spain
- REDINREN, Madrid, Spain
| | - Francisco J Lopez-Hernandez
- IRSIN, Madrid, Spain
- REDINREN, Madrid, Spain
- Biomedical Research Institute of Salamanca, University of Salamanca, Salamanca, Spain
| | - Marta Ruiz-Ortega
- Research Institute-Fundacion Jimenez Diaz, Autonoma University, Madrid, Spain
- IRSIN, Madrid, Spain
- REDINREN, Madrid, Spain
| | - Jesus Egido
- Research Institute-Fundacion Jimenez Diaz, Autonoma University, Madrid, Spain
- IRSIN, Madrid, Spain
| | - Alberto Ortiz
- Research Institute-Fundacion Jimenez Diaz, Autonoma University, Madrid, Spain
- IRSIN, Madrid, Spain
- REDINREN, Madrid, Spain
| | - Ana Belén Sanz
- Research Institute-Fundacion Jimenez Diaz, Autonoma University, Madrid, Spain
- IRSIN, Madrid, Spain
- REDINREN, Madrid, Spain
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27
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Chen J, Wei L, Xia Y. Roles of tumour necrosis factor-related weak inducer of apoptosis/fibroblast growth factor-inducible 14 pathway in lupus nephritis. Nephrology (Carlton) 2017; 22:101-106. [PMID: 27786399 DOI: 10.1111/nep.12957] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2016] [Revised: 10/20/2016] [Accepted: 10/23/2016] [Indexed: 02/06/2023]
Affiliation(s)
- Jingyun Chen
- Department of Dermatology, The Second Affiliated Hospital, School of Medicine; Xi'an Jiaotong University; Xi'an China
| | - Linlin Wei
- Core Research Laboratory, The Second Affiliated Hospital, School of Medicine; Xi'an Jiaotong University; Xi'an China
| | - Yumin Xia
- Department of Dermatology, The Second Affiliated Hospital, School of Medicine; Xi'an Jiaotong University; Xi'an China
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28
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Armstrong CL, Galisteo R, Brown SA, Winkles JA. TWEAK activation of the non-canonical NF-κB signaling pathway differentially regulates melanoma and prostate cancer cell invasion. Oncotarget 2016; 7:81474-81492. [PMID: 27821799 PMCID: PMC5348407 DOI: 10.18632/oncotarget.13034] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Accepted: 10/14/2016] [Indexed: 12/22/2022] Open
Abstract
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a multifunctional cytokine that binds with high affinity to a plasma membrane-anchored receptor named Fn14. Both TWEAK and Fn14 expression has been detected in human cancer tissue, and studies have shown that TWEAK/Fn14 signaling can promote either "pro-cancer" or "anti-cancer" cellular effects in vitro, depending on the cancer cell line under investigation. In this study, we engineered murine B16 melanoma cells to secrete high levels of soluble TWEAK and examined their properties. TWEAK production by B16 cells preferentially activated the non-canonical NF-κB signaling pathway and increased the expression of several previously described TWEAK-inducible genes, including Fn14. TWEAK overexpression in B16 cells inhibited both cell growth and invasion in vitro. The TWEAK-mediated reduction in B16 cell invasive capacity was dependent on activation of the non-canonical NF-κB signaling pathway. Finally, we found that this same signaling pathway was also important for TWEAK-stimulated human DU145 prostate cancer cell invasion. Therefore, even though TWEAK:Fn14 binding activates non-canonical NF-κB signaling in both melanoma and prostate cancer cells, this shared cellular response can trigger a very different downstream outcome (inhibition or stimulation of cell invasiveness, respectively).
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Affiliation(s)
- Cheryl L. Armstrong
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD, USA
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Rebeca Galisteo
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD, USA
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Sharron A.N. Brown
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD, USA
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Jeffrey A. Winkles
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD, USA
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
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29
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Ruiz-Andres O, Sanchez-Niño MD, Moreno JA, Ruiz-Ortega M, Ramos AM, Sanz AB, Ortiz A. Downregulation of kidney protective factors by inflammation: role of transcription factors and epigenetic mechanisms. Am J Physiol Renal Physiol 2016; 311:F1329-F1340. [PMID: 27760772 DOI: 10.1152/ajprenal.00487.2016] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Revised: 10/11/2016] [Accepted: 10/12/2016] [Indexed: 12/22/2022] Open
Abstract
Chronic kidney disease (CKD) is associated to an increased risk of death, CKD progression, and acute kidney injury (AKI) even from early stages, when glomerular filtration rate (GFR) is preserved. The link between early CKD and these risks is unclear, since there is no accumulation of uremic toxins. However, pathological albuminuria and kidney inflammation are frequent features of early CKD, and the production of kidney protective factors may be decreased. Indeed, Klotho expression is already decreased in CKD category G1 (normal GFR). Klotho has anti-aging and nephroprotective properties, and decreased Klotho levels may contribute to increase the risk of death, CKD progression, and AKI. In this review, we discuss the downregulation by mediators of inflammation of molecules with systemic and/or renal local protective functions, exemplified by Klotho and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a transcription factor that promotes mitochondrial biogenesis. Cytokines such as TWEAK, TNF-α, or transforming growth factor -β1 produced locally during kidney injury or released from inflammatory sites at other organs may decrease kidney expression of Klotho and PGC-1α or lead to suboptimal recruitment of these nephroprotective proteins. Transcription factors (e.g., Smad3 and NF-κB) and epigenetic mechanisms (e.g., histone acetylation or methylation) contribute to downregulate the expression of Klotho and/or PGC-1α, while histone crotonylation promotes PGC-1α expression. NF-κBiz facilitates the repressive effect of NF-κB on Klotho expression. A detailed understanding of these mediators may contribute to the development of novel therapeutic approaches to prevent CKD progression and its negative impact on mortality and AKI.
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Affiliation(s)
- Olga Ruiz-Andres
- IIS-Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid.,REDINREN, Madrid, Spain; and
| | - Maria Dolores Sanchez-Niño
- IIS-Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid.,REDINREN, Madrid, Spain; and
| | - Juan Antonio Moreno
- IIS-Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid
| | - Marta Ruiz-Ortega
- IIS-Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid.,REDINREN, Madrid, Spain; and
| | - Adrian Mario Ramos
- IIS-Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid.,REDINREN, Madrid, Spain; and
| | - Ana Belen Sanz
- IIS-Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid.,REDINREN, Madrid, Spain; and
| | - Alberto Ortiz
- IIS-Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid; .,REDINREN, Madrid, Spain; and.,Fundación Renal Iñigo Alvarez de Toledo-IRSIN, Madrid, Spain
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30
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Ortiz A, Husi H, Gonzalez-Lafuente L, Valiño-Rivas L, Fresno M, Sanz AB, Mullen W, Albalat A, Mezzano S, Vlahou T, Mischak H, Sanchez-Niño MD. Mitogen-Activated Protein Kinase 14 Promotes AKI. J Am Soc Nephrol 2016; 28:823-836. [PMID: 27620989 DOI: 10.1681/asn.2015080898] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2015] [Accepted: 07/28/2016] [Indexed: 01/20/2023] Open
Abstract
An improved understanding of pathogenic pathways in AKI may identify novel therapeutic approaches. Previously, we conducted unbiased liquid chromatography-tandem mass spectrometry-based protein expression profiling of the renal proteome in mice with acute folate nephropathy. Here, analysis of the dataset identified enrichment of pathways involving NFκB in the kidney cortex, and a targeted data mining approach identified components of the noncanonical NFκB pathway, including the upstream kinase mitogen-activated protein kinase kinase kinase 14 (MAP3K14), the NFκB DNA binding heterodimer RelB/NFκB2, and proteins involved in NFκB2 p100 ubiquitination and proteasomal processing to p52, as upregulated. Immunohistochemistry localized MAP3K14 expression to tubular cells in acute folate nephropathy and human AKI. In vivo, kidney expression levels of NFκB2 p100 and p52 increased rapidly after folic acid injection, as did DNA binding of RelB and NFκB2, detected in nuclei isolated from the kidneys. Compared with wild-type mice, MAP3K14 activity-deficient aly/aly (MAP3K14aly/aly) mice had less kidney dysfunction, inflammation, and apoptosis in acute folate nephropathy and less kidney dysfunction and a lower mortality rate in cisplatin-induced AKI. The exchange of bone marrow between wild-type and MAP3K14aly/aly mice did not affect the survival rate of either group after folic acid injection. In cultured tubular cells, MAP3K14 small interfering RNA targeting decreased inflammation and cell death. Additionally, cell culture and in vivo studies identified the chemokines MCP-1, RANTES, and CXCL10 as MAP3K14 targets in tubular cells. In conclusion, MAP3K14 promotes kidney injury through promotion of inflammation and cell death and is a promising novel therapeutic target.
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Affiliation(s)
- Alberto Ortiz
- Instituto Investigacion Sanitaria-Fundacion Jimenez Diaz-Universidad Autonoma de Madrid and Fundacion Renal Iñigo Alvarez de Toledo-Instituto Reina Sofia de Investigacion Nefrologica, Madrid, Spain; .,Red de Investigacion Rena, Madrid, Spain
| | - Holger Husi
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Laura Gonzalez-Lafuente
- Instituto Investigacion Sanitaria-Fundacion Jimenez Diaz-Universidad Autonoma de Madrid and Fundacion Renal Iñigo Alvarez de Toledo-Instituto Reina Sofia de Investigacion Nefrologica, Madrid, Spain.,Red de Investigacion Rena, Madrid, Spain
| | - Lara Valiño-Rivas
- Instituto Investigacion Sanitaria-Fundacion Jimenez Diaz-Universidad Autonoma de Madrid and Fundacion Renal Iñigo Alvarez de Toledo-Instituto Reina Sofia de Investigacion Nefrologica, Madrid, Spain.,Red de Investigacion Rena, Madrid, Spain
| | - Manuel Fresno
- Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas de la Universidad Autonoma de Madrid, Madrid, Spain
| | - Ana Belen Sanz
- Instituto Investigacion Sanitaria-Fundacion Jimenez Diaz-Universidad Autonoma de Madrid and Fundacion Renal Iñigo Alvarez de Toledo-Instituto Reina Sofia de Investigacion Nefrologica, Madrid, Spain.,Mosaiques diagnostics GmbH, Hannover, Germany
| | - William Mullen
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Amaya Albalat
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Sergio Mezzano
- Unidad de Nefrología, Instituto de Medicina, Universidad Austral de Chile, Valdivia, Chile; and
| | - Tonia Vlahou
- Biomedical Research Foundation Academy of Athens, Athens, Greece
| | - Harald Mischak
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.,Mosaiques diagnostics GmbH, Hannover, Germany
| | - Maria Dolores Sanchez-Niño
- Instituto Investigacion Sanitaria-Fundacion Jimenez Diaz-Universidad Autonoma de Madrid and Fundacion Renal Iñigo Alvarez de Toledo-Instituto Reina Sofia de Investigacion Nefrologica, Madrid, Spain; .,Red de Investigacion Rena, Madrid, Spain
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McDaniel DK, Eden K, Ringel VM, Allen IC. Emerging Roles for Noncanonical NF-κB Signaling in the Modulation of Inflammatory Bowel Disease Pathobiology. Inflamm Bowel Dis 2016; 22:2265-79. [PMID: 27508514 PMCID: PMC4992436 DOI: 10.1097/mib.0000000000000858] [Citation(s) in RCA: 118] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Crohn's disease and ulcerative colitis are common and debilitating manifestations of inflammatory bowel disease (IBD). IBD is characterized by a radical imbalance in the activation of proinflammatory and anti-inflammatory signaling pathways in the gut. These pathways are controlled by NF-κB, which is a master regulator of gene transcription. In IBD patients, NF-κB signaling is often dysregulated resulting in overzealous inflammation. NF-κB activation occurs through 2 distinct pathways, defined as either canonical or noncanonical. Canonical NF-κB pathway activation is well studied in IBD and is associated with the rapid, acute production of diverse proinflammatory mediators, such as COX-2, IL-1β, and IL-6. In contrast to the canonical pathway, the noncanonical or "alternative" NF-κB signaling cascade is tightly regulated and is responsible for the production of highly specific chemokines that tend to be associated with less acute, chronic inflammation. There is a relative paucity of literature regarding all aspects of noncanonical NF-ĸB signaling. However, it is clear that this alternative signaling pathway plays a considerable role in maintaining immune system homeostasis and likely contributes significantly to the chronic inflammation underlying IBD. Noncanonical NF-κB signaling may represent a promising new direction in the search for therapeutic targets and biomarkers associated with IBD. However, significant mechanistic insight is still required to translate the current basic science findings into effective therapeutic strategies.
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Affiliation(s)
- Dylan K. McDaniel
- Department of Biomedical Sciences and Pathobiology, Virginia Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24061
| | - Kristin Eden
- Department of Biomedical Sciences and Pathobiology, Virginia Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24061
| | - Veronica M. Ringel
- Graduate Program in Translational Biology, Medicine, and Health, Virginia Tech, Blacksburg, VA 24061
| | - Irving C. Allen
- Department of Biomedical Sciences and Pathobiology, Virginia Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24061
- Graduate Program in Translational Biology, Medicine, and Health, Virginia Tech, Blacksburg, VA 24061
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32
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Dutta P, Ta A, Thakur BK, Dasgupta N, Das S. Biphasic Ccl20 regulation by Toll-like receptor 9 through the activation of ERK-AP-1 and non-canonical NF-κB signaling pathways. Biochim Biophys Acta Gen Subj 2016; 1861:3365-3377. [PMID: 27590109 DOI: 10.1016/j.bbagen.2016.08.019] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Revised: 08/24/2016] [Accepted: 08/28/2016] [Indexed: 12/27/2022]
Abstract
BACKGROUND Chemokines play key roles in immune homeostasis and inflammatory response. Considering the role of Ccl20 and Toll-like receptor 9 (TLR9) in gut homeostasis and inflammatory bowel disease (IBD), regulation of Ccl20 by bacterial DNA, the TLR9 ligand, merits in-depth studies. METHODS We analyzed Ccl20 expression in various epithelial cell (EC) lines by q-PCR and ELISA. In-vivo expression was investigated in isolated murine colonocytes by immunoblotting. Transcriptional regulation of Ccl20 was studied by reporter assays, gene knock-down, electrophoretic mobility shift assay and chromatin immunoprecipitation. Activation of upstream kinases was checked by immunoblotting. RESULTS We showed low levels of Ccl20 expression in mouse colonic ECs, but marked induction by in vivo treatment with bacterial DNA. This corroborated with persistent Ccl20 induction in different EC lines. We found involvement of MAP-kinases during the early hours after stimulation, and a novel AP-1site (-252bp) regulated the expression in colonic ECs. More importantly, mutually exclusive transcriptional regulation by AP-1 (cjun/cfos) and non-canonical NF-κB (RelB/p52) downstream of MEK-ERK and NIK-IKK-α-NF-κB2 (p100) phosphorylation, respectively was responsible for persistent Ccl20 expression in the colonic cells, while canonical NF-κB isoforms played no role. CONCLUSIONS Persistent Ccl20 induction by TLR9 in colonic ECs involves early and delayed activation of two independent signaling pathways. This is the first report of non-canonical NF-κB activation and Ccl20 expression in the colonic ECs by TLR9. GENERAL SIGNIFICANCE Our study will help to better understand immune regulation by Ccl20 in the intestine and may be exploited for future development of novel therapeutics against IBD.
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Affiliation(s)
- Pujarini Dutta
- Division of Clinical Medicine, National Institute of Cholera and Enteric Diseases, Kolkata, India
| | - Atri Ta
- Division of Clinical Medicine, National Institute of Cholera and Enteric Diseases, Kolkata, India
| | - Bhupesh Kumar Thakur
- Division of Clinical Medicine, National Institute of Cholera and Enteric Diseases, Kolkata, India
| | - Nirmalya Dasgupta
- Division of Clinical Medicine, National Institute of Cholera and Enteric Diseases, Kolkata, India
| | - Santasabuj Das
- Division of Clinical Medicine, National Institute of Cholera and Enteric Diseases, Kolkata, India.
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TWEAK favors phosphate-induced calcification of vascular smooth muscle cells through canonical and non-canonical activation of NFκB. Cell Death Dis 2016; 7:e2305. [PMID: 27441657 PMCID: PMC4973358 DOI: 10.1038/cddis.2016.220] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Revised: 06/10/2016] [Accepted: 06/14/2016] [Indexed: 12/24/2022]
Abstract
Vascular calcification (VC) is associated with increased cardiovascular mortality in aging, chronic kidney disease (CKD), type 2 diabetes mellitus (T2DM) and atherosclerosis. TNF-like weak inducer of apoptosis (TWEAK) recently emerged as a new biomarker for the diagnosis and prognosis of cardiovascular diseases. TWEAK binding to its functional receptor Fn14 was reported to promote several steps of atherosclerotic plaque progression. However, no information is currently available on the role of TWEAK/Fn14 on the development of medial calcification, which is highly prevalent in aging, CKD and T2DM. This study explored the involvement of TWEAK in human vascular smooth muscle cells (h-VSMCs) calcification in vitro. We report that TWEAK binding to Fn14 promotes inorganic phosphate-induced h-VSMCs calcification, favors h-VSMCs osteogenic transition, decreasing acta2 and myh11 and increasing bmp2 mRNA and tissue non-specific alkaline phosphatase (TNAP), and increases MMP9 activity. Blockade of the canonical NFκB pathway reduced by 80% TWEAK pro-calcific properties and decreased osteogenic transition, TNAP and MMP9 activity. Blockade of non-canonical NFκB signaling by a siRNA targeting RelB reduced by 20% TWEAK pro-calcific effects and decreased TWEAK-induced loss of h-VSMCs contractile phenotype and MMP9 activity, without modulating bmp2 mRNA or TNAP activity. Inhibition of ERK1/2 activation by a MAPK kinase inhibitor did not influence TWEAK pro-calcific properties. Our results suggest that TWEAK/Fn14 directly favors inorganic phosphate-induced h-VSMCs calcification by activation of both canonical and non-canonical NFκB pathways. Given the availability of neutralizing anti-TWEAK strategies, our study sheds light on the TWEAK/Fn14 axis as a novel therapeutic target in the prevention of VC.
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Ta MHT, Schwensen KG, Liuwantara D, Huso DL, Watnick T, Rangan GK. Constitutive renal Rel/nuclear factor-κB expression in Lewis polycystic kidney disease rats. World J Nephrol 2016; 5:339-357. [PMID: 27458563 PMCID: PMC4936341 DOI: 10.5527/wjn.v5.i4.339] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Revised: 03/31/2016] [Accepted: 04/18/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine the temporal expression and pattern of Rel/nuclear factor (NF)-κB proteins in renal tissue in polycystic kidney disease (PKD).
METHODS: The renal expression of Rel/NF-κB proteins was determined by immunohistochemistry, immunofluorescence and immunoblot analysis in Lewis polycystic kidney rats (LPK, a genetic ortholog of human nephronopthsis-9) from postnatal weeks 3 to 20. At each timepoint, renal disease progression and the mRNA expression of NF-κB-dependent genes (TNFα and CCL2) were determined. NF-κB was also histologically assessed in human PKD tissue.
RESULTS: Progressive kidney enlargement in LPK rats was accompanied by increased renal cell proliferation and interstitial monocyte accumulation (peaking at weeks 3 and 10 respectively), and progressive interstitial fibrosis (with α smooth muscle actin and Sirius Red deposition significantly increased compared to Lewis kidneys from weeks 3 to 6 onwards). Rel/NF-κB proteins (phosphorylated-p105, p65, p50, c-Rel and RelB) were expressed in cystic epithelial cells (CECs) of LPK kidneys as early as postnatal week 3 and sustained until late-stage disease at week 20. From weeks 10 to 20, nuclear p65, p50, RelB and cytoplasmic IκBα protein levels, and TNFα and CCL2 expression, were upregulated in LPK compared to Lewis kidneys. NF-κB proteins were consistently expressed in CECs of human PKD. The DNA damage marker γ-H2AX was also identified in the CECs of LPK and human polycystic kidneys.
CONCLUSION: Several NF-κB proteins are consistently expressed in CECs in human and experimental PKD. These data suggest that the upregulation of both the canonical and non-canonical pathways of NF-κB signaling may be a constitutive and early pathological feature of cystic renal diseases.
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Valiño-Rivas L, Gonzalez-Lafuente L, Sanz AB, Ruiz-Ortega M, Ortiz A, Sanchez-Niño MD. Non-canonical NFκB activation promotes chemokine expression in podocytes. Sci Rep 2016; 6:28857. [PMID: 27353019 PMCID: PMC4926283 DOI: 10.1038/srep28857] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Accepted: 06/10/2016] [Indexed: 12/13/2022] Open
Abstract
TNF-like weak inducer of apoptosis (TWEAK) receptor Fn14 is expressed by podocytes and Fn14 deficiency protects from experimental proteinuric kidney disease. However, the downstream effectors of TWEAK/Fn14 in podocytes are poorly characterized. We have explored TWEAK activation of non-canonical NFκB signaling in cultured podocytes. In cultured podocytes, TWEAK increased the expression of the chemokines CCL21, CCL19 and RANTES in a time-dependent manner. The inhibitor of canonical NFκB activation parthenolide inhibited the CCL19 and the early RANTES responses, but not the CCL21 or late RANTES responses. In this regard, TWEAK induced non-canonical NFκB activation in podocytes, characterized by NFκB2/p100 processing to NFκB2/p52 and nuclear migration of RelB/p52. Silencing by a specific siRNA of NIK, the upstream kinase of the non-canonical NFκB pathway, prevented CCL21 upregulation but did not modulate CCL19 or RANTES expression in response to TWEAK, thus establishing CCL21 as a non-canonical NFκB target in podocytes. Increased kidney Fn14 and CCL21 expression was also observed in rat proteinuric kidney disease induced by puromycin, and was localized to podocytes. In conclusion, TWEAK activates the non-canonical NFκB pathway in podocytes, leading to upregulation of CCL21 expression. The non-canonical NFκB pathway should be explored as a potential therapeutic target in proteinuric kidney disease.
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Affiliation(s)
- Lara Valiño-Rivas
- IIS-Fundación Jiménez Díaz-Universidad Autónoma de Madrid and Fundación Renal Iñigo Alvarez de Toledo-IRSIN, Madrid, Spain.,REDINREN, Madrid, Spain
| | - Laura Gonzalez-Lafuente
- IIS-Fundación Jiménez Díaz-Universidad Autónoma de Madrid and Fundación Renal Iñigo Alvarez de Toledo-IRSIN, Madrid, Spain.,REDINREN, Madrid, Spain
| | - Ana B Sanz
- IIS-Fundación Jiménez Díaz-Universidad Autónoma de Madrid and Fundación Renal Iñigo Alvarez de Toledo-IRSIN, Madrid, Spain.,REDINREN, Madrid, Spain
| | - Marta Ruiz-Ortega
- IIS-Fundación Jiménez Díaz-Universidad Autónoma de Madrid and Fundación Renal Iñigo Alvarez de Toledo-IRSIN, Madrid, Spain.,REDINREN, Madrid, Spain
| | - Alberto Ortiz
- IIS-Fundación Jiménez Díaz-Universidad Autónoma de Madrid and Fundación Renal Iñigo Alvarez de Toledo-IRSIN, Madrid, Spain.,REDINREN, Madrid, Spain
| | - Maria D Sanchez-Niño
- IIS-Fundación Jiménez Díaz-Universidad Autónoma de Madrid and Fundación Renal Iñigo Alvarez de Toledo-IRSIN, Madrid, Spain.,REDINREN, Madrid, Spain
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Sanz AB, Ruiz-Andres O, Sanchez-Niño MD, Ruiz-Ortega M, Ramos AM, Ortiz A. Out of the TWEAKlight: Elucidating the Role of Fn14 and TWEAK in Acute Kidney Injury. Semin Nephrol 2016; 36:189-98. [DOI: 10.1016/j.semnephrol.2016.03.006] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Ruiz-Andres O, Sanchez-Niño MD, Cannata-Ortiz P, Ruiz-Ortega M, Egido J, Ortiz A, Sanz AB. Histone lysine crotonylation during acute kidney injury in mice. Dis Model Mech 2016; 9:633-45. [PMID: 27125278 PMCID: PMC4920150 DOI: 10.1242/dmm.024455] [Citation(s) in RCA: 94] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Accepted: 04/25/2016] [Indexed: 12/14/2022] Open
Abstract
Acute kidney injury (AKI) is a potentially lethal condition for which no therapy is available beyond replacement of renal function. Post-translational histone modifications modulate gene expression and kidney injury. Histone crotonylation is a recently described post-translational modification. We hypothesized that histone crotonylation might modulate kidney injury. Histone crotonylation was studied in cultured murine proximal tubular cells and in kidneys from mice with AKI induced by folic acid or cisplatin. Histone lysine crotonylation was observed in tubular cells from healthy murine and human kidney tissue. Kidney tissue histone crotonylation increased during AKI. This was reproduced by exposure to the protein TWEAK in cultured tubular cells. Specifically, ChIP-seq revealed enrichment of histone crotonylation at the genes encoding the mitochondrial biogenesis regulator PGC-1α and the sirtuin-3 decrotonylase in both TWEAK-stimulated tubular cells and in AKI kidney tissue. To assess the role of crotonylation in kidney injury, crotonate was used to increase histone crotonylation in cultured tubular cells or in the kidneys in vivo. Crotonate increased the expression of PGC-1α and sirtuin-3, and decreased CCL2 expression in cultured tubular cells and healthy kidneys. Systemic crotonate administration protected from experimental AKI, preventing the decrease in renal function and in kidney PGC-1α and sirtuin-3 levels as well as the increase in CCL2 expression. For the first time, we have identified factors such as cell stress and crotonate availability that increase histone crotonylation in vivo. Overall, increasing histone crotonylation might have a beneficial effect on AKI. This is the first observation of the in vivo potential of the therapeutic manipulation of histone crotonylation in a disease state. Summary: We have assessed the effect of the epigenetic post-translational modification histone crotonylation during kidney injury in vivo and in cell culture, and the involvement of PGC-1α and SIRT3 in the process.
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Affiliation(s)
- Olga Ruiz-Andres
- Nephrology, IIS-Fundacion Jimenez Diaz, Madrid 28040, Spain School of Medicine, UAM, Madrid 28029, Spain REDinREN, Madrid 28040, Spain
| | - Maria Dolores Sanchez-Niño
- Nephrology, IIS-Fundacion Jimenez Diaz, Madrid 28040, Spain School of Medicine, UAM, Madrid 28029, Spain REDinREN, Madrid 28040, Spain
| | - Pablo Cannata-Ortiz
- Pathology, IIS-Fundacion Jimenez Diaz, Madrid 28040, Spain School of Medicine, UAM, Madrid 28029, Spain
| | - Marta Ruiz-Ortega
- Nephrology, IIS-Fundacion Jimenez Diaz, Madrid 28040, Spain School of Medicine, UAM, Madrid 28029, Spain REDinREN, Madrid 28040, Spain IRSIN, Madrid 28003, Spain
| | - Jesus Egido
- Nephrology, IIS-Fundacion Jimenez Diaz, Madrid 28040, Spain School of Medicine, UAM, Madrid 28029, Spain IRSIN, Madrid 28003, Spain
| | - Alberto Ortiz
- Nephrology, IIS-Fundacion Jimenez Diaz, Madrid 28040, Spain School of Medicine, UAM, Madrid 28029, Spain REDinREN, Madrid 28040, Spain IRSIN, Madrid 28003, Spain
| | - Ana Belen Sanz
- Nephrology, IIS-Fundacion Jimenez Diaz, Madrid 28040, Spain School of Medicine, UAM, Madrid 28029, Spain REDinREN, Madrid 28040, Spain
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Gomez IG, Roach AM, Nakagawa N, Amatucci A, Johnson BG, Dunn K, Kelly MC, Karaca G, Zheng TS, Szak S, Peppiatt-Wildman CM, Burkly LC, Duffield JS. TWEAK-Fn14 Signaling Activates Myofibroblasts to Drive Progression of Fibrotic Kidney Disease. J Am Soc Nephrol 2016; 27:3639-3652. [PMID: 27026366 DOI: 10.1681/asn.2015111227] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Accepted: 02/16/2016] [Indexed: 01/15/2023] Open
Abstract
The identification of the cellular origins of myofibroblasts has led to the discovery of novel pathways that potentially drive myofibroblast perpetuation in disease. Here, we further investigated the role of innate immune signaling pathways in this process. In mice, renal injury-induced activation of pericytes, which are myofibroblast precursors attached to endothelial cells, led to upregulated expression of TNF receptor superfamily member 12a, also known as fibroblast growth factor-inducible 14 (Fn14), by these cells. In live rat kidney slices, administration of the Fn14 ligand, TNF-related weak inducer of apoptosis (TWEAK), promoted pericyte-dependent vasoconstriction followed by pericyte detachment from capillaries. In vitro, administration of TWEAK activated and differentiated pericytes into cytokine-producing myofibroblasts, and further activated established myofibroblasts in a manner requiring canonical and noncanonical NF-κB signaling pathways. Deficiency of Fn14 protected mouse kidneys from fibrogenesis, inflammation, and associated vascular instability after in vivo injury, and was associated with loss of NF-κB signaling. In a genetic model of spontaneous CKD, therapeutic delivery of anti-TWEAK blocking antibodies attenuated disease progression, preserved organ function, and increased survival. These results identify the TWEAK-Fn14 signaling pathway as an important factor in myofibroblast perpetuation, fibrogenesis, and chronic disease progression.
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Affiliation(s)
- Ivan G Gomez
- Research & Development, Biogen, Cambridge, Massachusetts.,Division of Nephrology, Departments of Medicine & Pathology, and Institute of Stem Cell & Regenerative Medicine, University of Washington, Seattle, Washington; and
| | - Allie M Roach
- Research & Development, Biogen, Cambridge, Massachusetts.,Division of Nephrology, Departments of Medicine & Pathology, and Institute of Stem Cell & Regenerative Medicine, University of Washington, Seattle, Washington; and
| | - Naoki Nakagawa
- Division of Nephrology, Departments of Medicine & Pathology, and Institute of Stem Cell & Regenerative Medicine, University of Washington, Seattle, Washington; and
| | - Aldo Amatucci
- Research & Development, Biogen, Cambridge, Massachusetts
| | - Bryce G Johnson
- Research & Development, Biogen, Cambridge, Massachusetts.,Division of Nephrology, Departments of Medicine & Pathology, and Institute of Stem Cell & Regenerative Medicine, University of Washington, Seattle, Washington; and
| | - Kadeshia Dunn
- Medway School of Pharmacy, University of Kent, Chatham, Kent, United Kingdom
| | - Mark C Kelly
- Medway School of Pharmacy, University of Kent, Chatham, Kent, United Kingdom
| | - Gamze Karaca
- Research & Development, Biogen, Cambridge, Massachusetts
| | | | - Suzanne Szak
- Research & Development, Biogen, Cambridge, Massachusetts
| | | | - Linda C Burkly
- Research & Development, Biogen, Cambridge, Massachusetts;
| | - Jeremy S Duffield
- Research & Development, Biogen, Cambridge, Massachusetts; .,Division of Nephrology, Departments of Medicine & Pathology, and Institute of Stem Cell & Regenerative Medicine, University of Washington, Seattle, Washington; and
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The inflammatory cytokine TWEAK decreases PGC-1α expression and mitochondrial function in acute kidney injury. Kidney Int 2016; 89:399-410. [DOI: 10.1038/ki.2015.332] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2015] [Revised: 09/03/2015] [Accepted: 09/10/2015] [Indexed: 12/11/2022]
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40
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Poveda J, Sanz AB, Rayego-Mateos S, Ruiz-Ortega M, Carrasco S, Ortiz A, Sanchez-Niño MD. NFκBiz protein downregulation in acute kidney injury: Modulation of inflammation and survival in tubular cells. Biochim Biophys Acta Mol Basis Dis 2016; 1862:635-646. [PMID: 26776679 DOI: 10.1016/j.bbadis.2016.01.006] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2015] [Revised: 12/18/2015] [Accepted: 01/06/2016] [Indexed: 11/29/2022]
Abstract
Acute kidney injury is characterized by decreased renal function, tubular cell death and interstitial inflammation. The transcription factor NF-κB is a key regulator of genes involved in cell survival and the inflammatory response. In order to better understand the regulation and role of NF-κB in acute kidney injury we explored the expression of NF-κB-related genes in experimental acute kidney injury induced by a folic acid overdose. NFκBiz, a member of the IκB family of NF-κB regulators encoding NFκBiz, was among the top up-regulated NF-κB-related genes at the mRNA level in experimental acute kidney injury. However, the NFκBiz protein was constitutively expressed by normal tubular cells but was down-regulated in experimental acute kidney injury. Kidney NFκBiz mRNA upregulation and protein downregulation was also observed in acute kidney injury induced by cisplatin or unilateral kidney injury resulting from ureteral obstruction. Thus, we studied the consequences of NFκBiz protein downregulation by specific siRNA in cultured tubular epithelial cells. NFκBiz mRNA and protein were up-regulated by inflammatory cytokines (IL-1β or TWEAK/TNFα/IFNγ) and by LPS in cultured tubular cells. However, TWEAK only induced a very mild and short lived NFκBiz upregulation. NFκBiz targeting increased chemokine production and dampened Klotho downregulation induced by TWEAK, without modulating cell proliferation. NFκBiz targeting also rendered cells more resistant to apoptosis induced by serum deprivation or inflammatory cytokines. In conclusion, NFκBiz differentially regulates NF-κB-mediated responses of tubular cells to inflammatory cytokines in a gene-specific manner, and may be of potential therapeutic interest to limit inflammation in kidney disease.
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Affiliation(s)
- Jonay Poveda
- IIS-Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid; Fundación Renal Iñigo Álvarez de Toledo-IRSIN and REDINREN, Madrid, Spain.
| | - Ana B Sanz
- IIS-Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid; Fundación Renal Iñigo Álvarez de Toledo-IRSIN and REDINREN, Madrid, Spain
| | - Sandra Rayego-Mateos
- IIS-Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid; Fundación Renal Iñigo Álvarez de Toledo-IRSIN and REDINREN, Madrid, Spain
| | - Marta Ruiz-Ortega
- IIS-Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid; Fundación Renal Iñigo Álvarez de Toledo-IRSIN and REDINREN, Madrid, Spain
| | - Susana Carrasco
- IIS-Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid; Fundación Renal Iñigo Álvarez de Toledo-IRSIN and REDINREN, Madrid, Spain
| | - Alberto Ortiz
- IIS-Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid; Fundación Renal Iñigo Álvarez de Toledo-IRSIN and REDINREN, Madrid, Spain.
| | - Maria D Sanchez-Niño
- IIS-Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid; Fundación Renal Iñigo Álvarez de Toledo-IRSIN and REDINREN, Madrid, Spain.
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Abstract
Nuclear factor κB (NF-κB) is a family of inducible transcription factors that plays a vital role in different aspects of immune responses. NF-κB is normally sequestered in the cytoplasm as inactive complexes via physical association with inhibitory proteins termed IκBs. In response to immune and stress stimuli, NF-κB members become activated via two major signaling pathways, the canonical and noncanonical pathways, and move to the nucleus to exert transcriptional functions. NF-κB is vital for normal immune responses against infections, but deregulated NF-κB activation is a major cause of inflammatory diseases. Accumulated studies suggest the involvement of NF-κB in the pathogenesis of renal inflammation caused by infection, injury, or autoimmune factors. In this review, we discuss the current understanding regarding the activation and function of NF-κB in different types of kidney diseases.
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Affiliation(s)
- Haisong Zhang
- />Department of Nephrology, Affiliated Hospital of Hebei University, No. 213 Yuhuadonglu, Baoding, 071000 China
| | - Shao-Cong Sun
- />Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, TX 77030 USA
- />The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030 USA
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Berzal S, González-Guerrero C, Rayego-Mateos S, Ucero Á, Ocaña-Salceda C, Egido J, Ortiz A, Ruiz-Ortega M, Ramos AM. TNF-related weak inducer of apoptosis (TWEAK) regulates junctional proteins in tubular epithelial cells via canonical NF-κB pathway and ERK activation. J Cell Physiol 2015; 230:1580-93. [PMID: 25536182 DOI: 10.1002/jcp.24905] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Accepted: 12/18/2014] [Indexed: 12/13/2022]
Abstract
The tubular epithelium may be intrinsically involved in promoting kidney injury by junctional instability, epithelial-mesenchymal transition (EMT) and extracellular matrix remodelling. In this work, we investigated whether the pleiotropic and proinflammatory cytokine tumor necrosis factor-like weak inducer of apoptosis (TWEAK), could be able to disturb junctional protein expression and to induce EMT of tubular cells. In cultured murine proximal tubular cells TWEAK induced phenotypic changes that were accompanied by F-actin redistribution, loss of epithelial adherent (E-cadherin, Cadherin-16, β-catenin) and tight junction (ZO-1) proteins, and re-expression of the mesenchymal protein Vimentin. The transcriptional repressors Snail and HNF1β were also modulated by TWEAK. In a murine model of obstructive renal pathology, TWEAK expression correlated with the appearance of the mesenchymal marker αSMA in kidney tubular cells. Mechanistically, the epithelial changes induced by TWEAK, including loss of epithelial integrity and EMT, via Fn14 were TGF-β1 independent, but mediated by several intracellular signaling systems, including the canonical NF-κB, ERK activation and the vitamin D receptor modulation. These results highlight potential contributions of TWEAK-induced inflammatory mechanisms that could unveil new pathogenic effects of TWEAK starting tubulointerstitial damage and fibrosis.
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Affiliation(s)
- Sergio Berzal
- Laboratory of Nephrology and Vascular Pathology, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain
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Ramos AM, González-Guerrero C, Sanz A, Sanchez-Niño MD, Rodríguez-Osorio L, Martín-Cleary C, Fernández-Fernández B, Ruiz-Ortega M, Ortiz A. Designing drugs that combat kidney damage. Expert Opin Drug Discov 2015; 10:541-56. [PMID: 25840605 DOI: 10.1517/17460441.2015.1033394] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Kidney disease remains one of the last worldwide frontiers in the field of non-communicable human disease. From 1990 to 2013, chronic kidney disease (CKD) was the top non-communicable cause of death with a greatest increase in global years of life lost while mortality of acute kidney injury (AKI) still hovers around 50%. This reflects the paucity (for CKD) or lack of (for AKI) therapeutic approaches beyond replacing renal function. Understanding what the barriers are and what potential pathways may facilitate the design of new drugs to combat kidney disease is a key public health priority. AREAS COVERED The authors discuss the hurdles and opportunities for future drug development for kidney disease in light of experience accumulated with drugs that made it to clinical trials. EXPERT OPINION Inflammation, cell death and fibrosis are key therapeutic targets to combat kidney damage. While the specific targeting of drugs to kidney cells would be desirable, the technology is only working at the preclinical stage and with mixed success. Nanomedicines hold promise in this respect. Most drugs undergoing clinical trials for kidney disease have been repurposed from other indications. Currently, the chemokine receptor inhibitor CCX140 holds promise for CKD and the p53 inhibitor QPI-1002 for AKI.
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Affiliation(s)
- Adrián M Ramos
- Instituto de Investigación Sanitaria-Fundación Jiménez Díaz (IIS-FJD), Laboratory of Renal and Vascular Pathology and Diabetes , Av. Reyes Católicos 2, 28040, Madrid , Spain
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Yadava RS, Foff EP, Yu Q, Gladman JT, Kim YK, Bhatt KS, Thornton CA, Zheng TS, Mahadevan MS. TWEAK/Fn14, a pathway and novel therapeutic target in myotonic dystrophy. Hum Mol Genet 2014; 24:2035-48. [PMID: 25504044 DOI: 10.1093/hmg/ddu617] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Myotonic dystrophy type 1 (DM1), the most prevalent muscular dystrophy in adults, is characterized by progressive muscle wasting and multi-systemic complications. DM1 is the prototype for disorders caused by RNA toxicity. Currently, no therapies exist. Here, we identify that fibroblast growth factor-inducible 14 (Fn14), a member of the tumor necrosis factor receptor super-family, is induced in skeletal muscles and hearts of mouse models of RNA toxicity and in tissues from DM1 patients, and that its expression correlates with severity of muscle pathology. This is associated with downstream signaling through the NF-κB pathways. In mice with RNA toxicity, genetic deletion of Fn14 results in reduced muscle pathology and better function. Importantly, blocking TWEAK/Fn14 signaling with an anti-TWEAK antibody likewise improves muscle histopathology and functional outcomes in affected mice. These results reveal new avenues for therapeutic development and provide proof of concept for a novel therapeutic target for which clinically available therapy exists to potentially treat muscular dystrophy in DM1.
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Affiliation(s)
| | - Erin P Foff
- Department of Neurology, University of Virginia, Charlottesville, VA 22908, USA
| | | | | | | | - Kirti S Bhatt
- Department of Neurology, University of Rochester, Rochester, NY 14642, USA and
| | - Charles A Thornton
- Department of Neurology, University of Rochester, Rochester, NY 14642, USA and
| | - Timothy S Zheng
- Department of Immunology, Biogen Idec, Cambridge, MA 02142, USA
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Sanz AB, Izquierdo MC, Sanchez-Niño MD, Ucero AC, Egido J, Ruiz-Ortega M, Ramos AM, Putterman C, Ortiz A. TWEAK and the progression of renal disease: clinical translation. Nephrol Dial Transplant 2014; 29 Suppl 1:i54-i62. [PMID: 24493870 DOI: 10.1093/ndt/gft342] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) activates the fibroblast growth factor-inducible-14 (Fn14) receptor. TWEAK has actions on intrinsic kidney cells and on inflammatory cells of potential pathophysiological relevance. The effects of TWEAK in tubular cells have been explored in most detail. In cultured murine tubular cells TWEAK induces the expression of inflammatory cytokines, downregulates the expression of Klotho, is mitogenic, and in the presence of sensitizing agents promotes apoptosis. Similar actions were observed on glomerular mesangial cells. In vivo TWEAK actions on healthy kidneys mimic cell culture observations. Increased expression of TWEAK and Fn14 was reported in human and experimental acute and chronic kidney injury. The role of TWEAK/Fn14 in kidney injury has been demonstrated in non-inflammatory compensatory renal growth, acute kidney injury and chronic kidney disease of immune and non-immune origin, including hyperlipidaemic nephropathy, lupus nephritis (LN) and anti-GBM nephritis. The nephroprotective effect of TWEAK or Fn14 targeting in immune-mediated kidney injury is the result of protection from TWEAK-induced injury of renal intrinsic cells, not from interference with the immune response. A phase I dose-ranging clinical trial demonstrated the safety of anti-TWEAK antibodies in humans. A phase II randomized placebo-controlled clinical trial exploring the efficacy, safety and tolerability of neutralizing anti-TWEAK antibodies as a tissue protection strategy in LN is ongoing. The eventual success of this trial may expand the range of kidney diseases in which TWEAK targeting should be explored.
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Affiliation(s)
- Ana B Sanz
- Dialysis Unit, IIS-Fundacion Jimenez Diaz, Madrid, Spain
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Wajant H. The TWEAK-Fn14 system as a potential drug target. Br J Pharmacol 2014; 170:748-64. [PMID: 23957828 DOI: 10.1111/bph.12337] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2013] [Revised: 07/29/2013] [Accepted: 08/12/2013] [Indexed: 12/27/2022] Open
Abstract
Fibroblast growth factor-inducible 14 (Fn14) is a member of the tumour necrosis factor (TNF) receptor family that is induced in a variety of cell types in situations of tissue injury. Fn14 becomes activated by TNF-like weak inducer of apoptosis (TWEAK), a typical member of the TNF ligand family. TWEAK is constitutively expressed by monocytes and some tumour cell lines and also shows cytokine inducible expression in various other cell types. Fn14 activation results in stimulation of signalling pathways culminating in the activation of NFκB transcription factors and various MAPKs but might also trigger the PI3K/Akt pathway and GTPases of the Rho family. In accordance with its tissue damage-associated expression pattern and its pleiotropic proinflammatory signalling capabilities, the TWEAK-Fn14 system has been implicated in a huge number of pathologies. The use of TWEAK- and Fn14-knockout mice identified the TWEAK-Fn14 system as a crucial player in muscle atrophy, cerebral ischaemia, kidney injury, atherosclerosis and infarction as well as in various autoimmune scenarios including experimental autoimmune encephalitis, rheumatoid arthritis and inflammatory bowel disease. Moreover, there is increasing preclinical evidence that Fn14 targeting is a useful option in tumour therapy. Based on a discussion of the signalling capabilities of TWEAK and Fn14, this review is focused on two major issues. On the one hand, on the molecular and cellular basis of the TWEAK/Fn14-related pathological outcomes in the aforementioned diseases and on the other hand, on the preclinical experience that have been made so far with TWEAK and Fn14 targeting drugs.
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Affiliation(s)
- Harald Wajant
- Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany
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Abstract
Acute kidney injury (AKI) is a serious clinical condition with no effective treatment. Tubular cells are key targets in AKI. Tubular cells and, specifically, proximal tubular cells are extremely rich in mitochondria and mitochondrial changes had long been known to be a feature of AKI. However, only recent advances in understanding the molecules involved in mitochondria biogenesis and dynamics and the availability of mitochondria-targeted drugs has allowed the exploration of the specific role of mitochondria in AKI. We now review the morphological and functional mitochondrial changes during AKI, as well as changes in the expression of mitochondrial genes and proteins. Finally, we summarise the current status of novel therapeutic strategies specifically targeting mitochondria such as mitochondrial permeability transition pore (MPTP) opening inhibitors (cyclosporine A (CsA)), quinone analogues (MitoQ, SkQ1 and SkQR1), superoxide dismutase (SOD) mimetics (Mito-CP), Szeto-Schiller (SS) peptides (Bendavia) and mitochondrial division inhibitors (mdivi-1). MitoQ, SkQ1, SkQR1, Mito-CP, Bendavia and mdivi-1 have improved the course of diverse experimental models of AKI. Evidence for a beneficial effect of CsA on human cardiac ischaemia-reperfusion injury derives from a clinical trial; however, CsA is nephrotoxic. MitoQ and Bendavia have been shown to be safe for humans. Ongoing clinical trials are testing the efficacy of Bendavia in AKI prevention following renal artery percutaneous transluminal angioplasty.
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Abstract
PURPOSE OF REVIEW The tumor necrosis factor-like weak inducer of apoptosis (TWEAK) cytokine has been linked to kidney injury by functional studies in experimental animals, and has biomarker potential in kidney disease. RECENT FINDINGS TWEAK was known to promote tubular cell injury and kidney inflammation. Recent studies have expanded these observations, identifying additional targets of TWEAK relevant to kidney injury. Thus, TWEAK upregulates the chemokine and cholesterol scavenger receptor CXCL16 and downregulates the antiaging and antifibrotic molecule Klotho in tubular cells. Furthermore, fibrogenic TWEAK actions on renal fibroblasts were described. TWEAK or factor-inducible molecule 14 targeting decreased the kidney fibrosis resulting from immune and nonimmune kidney injury induced by transient tubular or glomerular insults or by persistent urinary tract obstruction. TWEAK might also contribute to the link between chronic kidney disease and kidney cancer, as suggested by its role in other genitourinary cancers. Progress has also been made in TWEAK targeting. A phase I clinical trial showed that TWEAK targeting is well tolerated in humans, and an ongoing trial is exploring efficacy in lupus nephritis. Nanomolecules and inhibitors of epidermal growth factor receptor pathway may also protect from the adverse effects of TWEAK in the kidney. SUMMARY These findings suggest that TWEAK targeting has clinical potential in kidney injury of immune and nonimmune origin.
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Martín P, Mora I, Cortes MA, Calleros L, García-Jerez A, Ortiz A, Rodríguez-Puyol M, Rodríguez-Puyol D, Olmos G. Relevant role of PKG in the progression of fibrosis induced by TNF-like weak inducer of apoptosis. Am J Physiol Renal Physiol 2014; 307:F75-85. [DOI: 10.1152/ajprenal.00398.2013] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
TNF-like weak inducer of apoptosis (TWEAK) is an inflammatory cytokine that activates the FGF-inducible 14 receptor. Both TWEAK and the FGF-inducible 14 receptor are constitutively expressed in the kidney. TWEAK has been shown to modulate several biological responses, such as inflammation, proliferation, differentiation, and apoptosis, that contribute to kidney injury. However, the role of TWEAK in fibrosis and TWEAK-activated intracellular signaling pathways remain poorly understood. We tested the hypothesis that TWEAK can be a potent inducer of renal fibrosis by increasing transforming growth factor (TGF)-β1 expression (a well-known switch in the fibrosis process) through PKG-I downregulation. We showed that in human mesangial cells, TWEAK increased TGF-β1 expression and activity, leading to higher levels of the extracellular matrix protein fibronectin and decreased PKG-I expression and activity via the Ras pathway. PKG-I activation with 8-bromo-cGMP, Ras inactivation with dominant negative Ras, or Ras pathway inhibition with the ERK1/2 inhibitor PD-98059 resulted in the prevention of TWEAK-induced TGF-β1 upregulation. In vivo, exogenous administration of TWEAK to wild-type mice downregulated kidney PKG-I and increased kidney TGF-β1 expression. These effects were blunted in H-Ras knockout mice. Together, these data demonstrate, for the first time, the key role of PKG-I in TGF-β1 induction by TWEAK in kidney cells.
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Affiliation(s)
- Paloma Martín
- Department of System Biology, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
- REDinREN (Instituto de Salud Carlos III), Madrid, Spain
- Instituto Reina Sofía de Investigaciones Nefrológicas, Madrid, Spain
| | - Inés Mora
- REDinREN (Instituto de Salud Carlos III), Madrid, Spain
- Instituto Reina Sofía de Investigaciones Nefrológicas, Madrid, Spain
| | - M. Alicia Cortes
- Department of System Biology, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
- REDinREN (Instituto de Salud Carlos III), Madrid, Spain
- Instituto Reina Sofía de Investigaciones Nefrológicas, Madrid, Spain
| | - Laura Calleros
- Department of System Biology, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
- REDinREN (Instituto de Salud Carlos III), Madrid, Spain
- Instituto Reina Sofía de Investigaciones Nefrológicas, Madrid, Spain
| | - Andrea García-Jerez
- Department of System Biology, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
- REDinREN (Instituto de Salud Carlos III), Madrid, Spain
- Instituto Reina Sofía de Investigaciones Nefrológicas, Madrid, Spain
| | - Alberto Ortiz
- REDinREN (Instituto de Salud Carlos III), Madrid, Spain
- IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain
| | - Manuel Rodríguez-Puyol
- Department of System Biology, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
- REDinREN (Instituto de Salud Carlos III), Madrid, Spain
- Instituto Reina Sofía de Investigaciones Nefrológicas, Madrid, Spain
| | - Diego Rodríguez-Puyol
- REDinREN (Instituto de Salud Carlos III), Madrid, Spain
- Instituto Reina Sofía de Investigaciones Nefrológicas, Madrid, Spain
- Department of Medicine, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
- Nephrology Section and Research Unit, Hospital Príncipe de Asturias, Alcalá de Henares, Madrid, Spain; and
| | - Gemma Olmos
- Department of System Biology, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
- REDinREN (Instituto de Salud Carlos III), Madrid, Spain
- Instituto Reina Sofía de Investigaciones Nefrológicas, Madrid, Spain
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Sanz AB, Aroeira LS, Bellon T, del Peso G, Jimenez-Heffernan J, Santamaria B, Sanchez-Niño MD, Blanco-Colio LM, Lopez-Cabrera M, Ruiz-Ortega M, Egido J, Selgas R, Ortiz A. TWEAK promotes peritoneal inflammation. PLoS One 2014; 9:e90399. [PMID: 24599047 PMCID: PMC3944020 DOI: 10.1371/journal.pone.0090399] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Accepted: 01/29/2014] [Indexed: 02/02/2023] Open
Abstract
Peritoneal dialysis (PD) is complicated by peritonitis episodes that cause loss of mesothelium and eventually sclerosing peritonitis. An improved understanding of the molecular contributors to peritoneal injury and defense may increase the therapeutic armamentarium to optimize peritoneal defenses while minimizing peritoneal injury. There is no information on the expression and function of the cytokine TWEAK and its receptor Fn14 during peritoneal injury. Fn14 expression and soluble TWEAK levels were measured in human PD peritoneal effluent cells or fluids with or without peritonitis. Fn14 expression was also analyzed in peritoneal biopsies from PD patients. Actions of intraperitoneal TWEAK were studied in mice in vivo. sTWEAK levels were increased in peritoneal effluent in PD peritonitis. Effluent sTWEAK levels correlated with the number of peritoneal macrophages (r = 0.491, p = 0.002). Potential TWEAK targets that express the receptor Fn14 include mesothelial cells and macrophages, as demonstrated by flow cytometry of peritoneal effluents and by analysis of peritoneal biopsies. Peritoneal biopsy Fn14 correlated with mesothelial injury, fibrosis and inflammation, suggesting a potential deleterious effect of TWEAK/Fn14. In this regard, intraperitoneal TWEAK administration to mice promoted peritoneal inflammation characterized by increased peritoneal effluent MCP-1, Fn14 and Gr1+ macrophages, increased mesothelial Fn14, MCP-1 and CCL21 expression and submesothelial tissue macrophage recruitment. Taken together these data suggest that the TWEAK/Fn14 system may promote inflammation and tissue injury during peritonitis and PD.
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Affiliation(s)
- Ana Belen Sanz
- Laboratory of Nephrology, IIS-Fundacion Jimenez Diaz, Madrid, Spain
- REDinREN, Madrid, Spain
- * E-mail:
| | - Luiz Stark Aroeira
- Department of Immunology, Instituto de Investigación Biomédica de Vigo (IBIV), Vigo, Pontevedra, Spain
| | | | - Gloria del Peso
- Department of Nephrology, IDIPAZ, Madrid, Spain
- REDinREN, Madrid, Spain
| | | | | | | | | | | | - Marta Ruiz-Ortega
- Laboratory of Nephrology, IIS-Fundacion Jimenez Diaz, Madrid, Spain
- REDinREN, Madrid, Spain
- Universidad Autonoma de Madrid, Madrid, Spain
| | - Jesus Egido
- Laboratory of Nephrology, IIS-Fundacion Jimenez Diaz, Madrid, Spain
- Universidad Autonoma de Madrid, Madrid, Spain
- IRSIN, Madrid, Spain
| | - Rafael Selgas
- Department of Nephrology, IDIPAZ, Madrid, Spain
- REDinREN, Madrid, Spain
- Universidad Autonoma de Madrid, Madrid, Spain
- IRSIN, Madrid, Spain
| | - Alberto Ortiz
- Laboratory of Nephrology, IIS-Fundacion Jimenez Diaz, Madrid, Spain
- REDinREN, Madrid, Spain
- Universidad Autonoma de Madrid, Madrid, Spain
- IRSIN, Madrid, Spain
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