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McCoy MD, Sarasua SM, DeLuca JM, Davis S, Rogers RC, Phelan K, Boccuto L. Genetics of kidney disorders in Phelan-McDermid syndrome: evidence from 357 registry participants. Pediatr Nephrol 2024; 39:749-760. [PMID: 37733098 DOI: 10.1007/s00467-023-06146-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 08/07/2023] [Accepted: 08/22/2023] [Indexed: 09/22/2023]
Abstract
BACKGROUND Phelan-McDermid syndrome (PMS) is a rare genetic disorder caused by SHANK3 pathogenic variants or chromosomal rearrangements affecting the chromosome 22q13 region. Previous research found that kidney disorders, primarily congenital anomalies of the kidney and urinary tract, are common in people with PMS, yet research into candidate genes has been hampered by small study sizes and lack of attention to these problems. METHODS We used a cohort of 357 people from the Phelan-McDermid Syndrome Foundation International Registry to investigate the prevalence of kidney disorders in PMS using a cross-sectional design and to identify 22q13 genes contributing to these disorders. RESULTS Kidney disorders reported included vesicoureteral reflux (n = 37), hydronephrosis (n = 36), dysplastic kidneys (n = 19), increased kidney size (n = 19), polycystic kidneys (15 cases), and kidney stones (n = 4). Out of 315 subjects with a 22q13 deletion, 101 (32%) had at least one kidney disorder, while only one out of 42 (2%) individuals with a SHANK3 pathogenic variant had a kidney disorder (increased kidney size). We identified two genomic regions that were significantly associated with having a kidney disorder with the peak associations observed near positions approximately 5 Mb and 400 Kb from the telomere. CONCLUSIONS The candidate genes for kidney disorders include FBLN1, WNT7B, UPK3A, CELSR1, and PLXNB2. This study demonstrates the utility of patient registries for uncovering genetic contributions to rare diseases. Future work should focus on functional studies for these genes to assess their potential pathogenic contribution to the different subsets of kidney disorders.
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Affiliation(s)
- Megan D McCoy
- School of Nursing, Healthcare Genetics Program, Clemson University, Clemson, SC, 29634, USA
| | - Sara M Sarasua
- School of Nursing, Healthcare Genetics Program, Clemson University, Clemson, SC, 29634, USA.
| | - Jane M DeLuca
- School of Nursing, Healthcare Genetics Program, Clemson University, Clemson, SC, 29634, USA
| | - Stephanie Davis
- School of Nursing, Healthcare Genetics Program, Clemson University, Clemson, SC, 29634, USA
| | | | - Katy Phelan
- Genetics Laboratory, Florida Cancer Specialists and Research Institute, Fort Myers, FL, 33916, USA
| | - Luigi Boccuto
- School of Nursing, Healthcare Genetics Program, Clemson University, Clemson, SC, 29634, USA
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van Heugten MH, Blijdorp CJ, Arjune S, van Willigenburg H, Bezstarosti K, Demmers JA, Musterd-Bhaggoe U, Meijer E, Gansevoort RT, Zietse R, Hayat S, Kramann R, Müller RU, Salih M, Hoorn EJ. Matrix Metalloproteinase-7 in Urinary Extracellular Vesicles Identifies Rapid Disease Progression in Autosomal Dominant Polycystic Kidney Disease. J Am Soc Nephrol 2024; 35:321-334. [PMID: 38073039 PMCID: PMC10914202 DOI: 10.1681/asn.0000000000000277] [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: 05/17/2023] [Accepted: 11/12/2023] [Indexed: 03/02/2024] Open
Abstract
SIGNIFICANCE STATEMENT There is an unmet need for biomarkers of disease progression in autosomal dominant polycystic kidney disease (ADPKD). This study investigated urinary extracellular vesicles (uEVs) as a source of such biomarkers. Proteomic analysis of uEVs identified matrix metalloproteinase 7 (MMP-7) as a biomarker predictive of rapid disease progression. In validation studies, MMP-7 was predictive in uEVs but not in whole urine, possibly because uEVs are primarily secreted by tubular epithelial cells. Indeed, single-nucleus RNA sequencing showed that MMP-7 was especially increased in proximal tubule and thick ascending limb cells, which were further characterized by a profibrotic phenotype. Together, these data suggest that MMP-7 is a biologically plausible and promising uEV biomarker for rapid disease progression in ADPKD. BACKGROUND In ADPKD, there is an unmet need for early markers of rapid disease progression to facilitate counseling and selection for kidney-protective therapy. Our aim was to identify markers for rapid disease progression in uEVs. METHODS Six paired case-control groups ( n =10-59/group) of cases with rapid disease progression and controls with stable disease were formed from two independent ADPKD cohorts, with matching by age, sex, total kidney volume, and genetic variant. Candidate uEV biomarkers were identified by mass spectrometry and further analyzed using immunoblotting and an ELISA. Single-nucleus RNA sequencing of healthy and ADPKD tissue was used to identify the cellular origin of the uEV biomarker. RESULTS In the discovery proteomics experiments, the protein abundance of MMP-7 was significantly higher in uEVs of patients with rapid disease progression compared with stable disease. In the validation groups, a significant >2-fold increase in uEV-MMP-7 in patients with rapid disease progression was confirmed using immunoblotting. By contrast, no significant difference in MMP-7 was found in whole urine using ELISA. Compared with healthy kidney tissue, ADPKD tissue had significantly higher MMP-7 expression in proximal tubule and thick ascending limb cells with a profibrotic phenotype. CONCLUSIONS Among patients with ADPKD, rapid disease progressors have higher uEV-associated MMP-7. Our findings also suggest that MMP-7 is a biologically plausible biomarker for more rapid disease progression.
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Affiliation(s)
- Martijn H. van Heugten
- Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Charles J. Blijdorp
- Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Sita Arjune
- Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- Faculty of Medicine and University Hospital Cologne, Center for Rare Diseases Cologne, University of Cologne, Cologne, Germany
| | - Hester van Willigenburg
- Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Karel Bezstarosti
- Proteomics Center, Erasmus Medical Center, Rotterdam, The Netherlands
| | | | - Usha Musterd-Bhaggoe
- Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Esther Meijer
- Department of Internal Medicine, University Medical Center Groningen, Groningen, The Netherlands
| | - Ron T. Gansevoort
- Department of Internal Medicine, University Medical Center Groningen, Groningen, The Netherlands
| | - Robert Zietse
- Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Sikander Hayat
- Medical Faculty, Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany
| | - Rafael Kramann
- Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
- Medical Faculty, Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany
- Division of Nephrology, RWTH Aachen University, Aachen, Germany
| | - Roman-Ulrich Müller
- Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- Faculty of Medicine and University Hospital Cologne, Center for Rare Diseases Cologne, University of Cologne, Cologne, Germany
| | - Mahdi Salih
- Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Ewout J. Hoorn
- Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
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Pala R, Barui AK, Mohieldin AM, Zhou J, Nauli SM. Folate conjugated nanomedicines for selective inhibition of mTOR signaling in polycystic kidneys at clinically relevant doses. Biomaterials 2023; 302:122329. [PMID: 37722182 PMCID: PMC10836200 DOI: 10.1016/j.biomaterials.2023.122329] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 09/12/2023] [Indexed: 09/20/2023]
Abstract
Although rapamycin is a very effective drug for rodents with polycystic kidney disease (PKD), it is not encouraging in the clinical trials due to the suboptimal dosages compelled by the off-target side effects. We here report the generation, characterization, specificity, functionality, pharmacokinetic, pharmacodynamic and toxicology profiles of novel polycystic kidney-specific-targeting nanoparticles (NPs). We formulated folate-conjugated PLGA-PEG NPs, which can be loaded with multiple drugs, including rapamycin (an mTOR inhibitor) and antioxidant 4-hydroxy-TEMPO (a nephroprotective agent). The NPs increased the efficacy, potency and tolerability of rapamycin resulting in an increased survival rate and improved kidney function by decreasing side effects and reducing biodistribution to other organs in PKD mice. The daily administration of rapamycin-alone (1 mg/kg/day) could now be achieved with a weekly injection of NPs containing rapamycin (379 μg/kg/week). This polycystic kidney-targeting nanotechnology, for the first time, integrated advances in the use of 1) nanoparticles as a delivery cargo, 2) folate for targeting, 3) near-infrared Cy5-fluorophore for in vitro and in vivo live imaging, 4) rapamycin as a pharmacological therapy, and 5) TEMPO as a combinational therapy. The slow sustained-release of rapamycin by polycystic kidney-targeting NPs demonstrates a new era of nanomedicine in treatment for chronic kidney diseases at clinically relevant doses.
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Affiliation(s)
- Rajasekharreddy Pala
- Department of Biomedical and Pharmaceutical Sciences, Chapman University, Irvine, CA, 92618, USA; Marlin Biopharma, Irvine, CA, 92620, USA.
| | - Ayan K Barui
- Department of Biomedical and Pharmaceutical Sciences, Chapman University, Irvine, CA, 92618, USA
| | - Ashraf M Mohieldin
- Department of Biomedical and Pharmaceutical Sciences, Chapman University, Irvine, CA, 92618, USA
| | - Jing Zhou
- Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA
| | - Surya M Nauli
- Department of Biomedical and Pharmaceutical Sciences, Chapman University, Irvine, CA, 92618, USA; Marlin Biopharma, Irvine, CA, 92620, USA.
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Wang J, Zhou P, Zhu L, Guan H, Gou J, Liu X. Maternal protein deficiency alters primary cilia length in renal tubular and impairs kidney development in fetal rat. Front Nutr 2023; 10:1156029. [PMID: 37485393 PMCID: PMC10358357 DOI: 10.3389/fnut.2023.1156029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 06/21/2023] [Indexed: 07/25/2023] Open
Abstract
Introduction Intrauterine malnutrition impairs embryo kidney development and leads to kidney disease and hypertension in adulthood, yet the underlying mechanism remains unclear. Methods With a maternal protein restriction (MPR) rat model, we investigated the critical ciliogenesis factors and β-catenin pathway in FGR fetal kidneys and analyzed the impact of aberrant primary cilia on renal tubular epithelium. Results The data showed decreased nephron number and renal tubular dysgenesis in FGR fetus. FGR fetus showed deregulated expression of ciliogenesis factors including upregulation of IFT88 and downregulation of DYNLT1, accompanied with cilia elongation in renal tubular epithelial cells. Wnt7b, the key ligand for Wnt/β-catenin signaling, was downregulated and nuclear translocation of β-catenin was decreased. The proapoptotic protein was upregulated. In vitro study with HK-2 cells showed that overexpression of IFT88 lengthened the cilia, inhibited β-catenin signaling. Besides, IFT88 overexpression suppressed cell proliferation, activated autophagy, and induced cell apoptosis. Inhibition of autophagy partly restored the cilia length and cell viability. Likewise, knockdown of DYNLT1 led to cilia elongation, suppressed cell proliferation, and promoted apoptosis in HK-2 cell. However, the cilia elongation induced by DYNLT1 knockdown was not autophagy-dependent, but associated with reactive oxygen species (ROS) accumulation. Discussion We elucidated that intrauterine protein malnutrition led to deregulation of ciliogenesis factors and cilia elongation in renal tubular epithelial, inhibited β-catenin signaling, and induced cell apoptosis and ultimately, compromised kidney development.
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Affiliation(s)
- Jun Wang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Pei Zhou
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Liangliang Zhu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Hongbo Guan
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jian Gou
- Department of Nutrition, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xiaomei Liu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
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Zhou X, Torres VE. Emerging therapies for autosomal dominant polycystic kidney disease with a focus on cAMP signaling. Front Mol Biosci 2022; 9:981963. [PMID: 36120538 PMCID: PMC9478168 DOI: 10.3389/fmolb.2022.981963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 08/05/2022] [Indexed: 11/29/2022] Open
Abstract
Autosomal dominant polycystic kidney disease (ADPKD), with an estimated genetic prevalence between 1:400 and 1:1,000 individuals, is the third most common cause of end stage kidney disease after diabetes mellitus and hypertension. Over the last 3 decades there has been great progress in understanding its pathogenesis. This allows the stratification of therapeutic targets into four levels, gene mutation and polycystin disruption, proximal mechanisms directly caused by disruption of polycystin function, downstream regulatory and signaling pathways, and non-specific pathophysiologic processes shared by many other diseases. Dysfunction of the polycystins, encoded by the PKD genes, is closely associated with disruption of calcium and upregulation of cyclic AMP and protein kinase A (PKA) signaling, affecting most downstream regulatory, signaling, and pathophysiologic pathways altered in this disease. Interventions acting on G protein coupled receptors to inhibit of 3',5'-cyclic adenosine monophosphate (cAMP) production have been effective in preclinical trials and have led to the first approved treatment for ADPKD. However, completely blocking cAMP mediated PKA activation is not feasible and PKA activation independently from cAMP can also occur in ADPKD. Therefore, targeting the cAMP/PKA/CREB pathway beyond cAMP production makes sense. Redundancy of mechanisms, numerous positive and negative feedback loops, and possibly counteracting effects may limit the effectiveness of targeting downstream pathways. Nevertheless, interventions targeting important regulatory, signaling and pathophysiologic pathways downstream from cAMP/PKA activation may provide additive or synergistic value and build on a strategy that has already had success. The purpose of this manuscript is to review the role of cAMP and PKA signaling and their multiple downstream pathways as potential targets for emergent therapies for ADPKD.
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Affiliation(s)
- Xia Zhou
- Mayo Clinic, Department of Nephrology, Rochester, MN, United States
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Dixon EE, Bradford STJ, Humphreys BD. Mini kidney organoids deliver maximal drug screening impact. Cell Stem Cell 2022; 29:1011-1012. [PMID: 35803221 DOI: 10.1016/j.stem.2022.06.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
In this issue of Cell Stem Cell, Tran and colleagues develop a platform for differentiating thousands of miniature kidney organoids consisting of one or two nephron-like structures each. They use this platform to identify a potent new inhibitor of cyst growth in organoid models of autosomal-dominant polycystic kidney disease.
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Affiliation(s)
- Eryn E Dixon
- Division of Nephrology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA
| | - Shayna T J Bradford
- Division of Nephrology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA
| | - Benjamin D Humphreys
- Division of Nephrology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA; Department of Developmental Biology, Washington University in St. Louis, St. Louis, MO, USA.
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Nardozi D, Palumbo S, Khan AUM, Sticht C, Bieback K, Sadeghi S, Kluth MA, Keese M, Gretz N. Potential Therapeutic Effects of Long-Term Stem Cell Administration: Impact on the Gene Profile and Kidney Function of PKD/Mhm (Cy/+) Rats. J Clin Med 2022; 11:jcm11092601. [PMID: 35566725 PMCID: PMC9102853 DOI: 10.3390/jcm11092601] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 04/26/2022] [Accepted: 05/03/2022] [Indexed: 11/16/2022] Open
Abstract
Cystic kidney disease (CKD) is a heterogeneous group of genetic disorders and one of the most common causes of end-stage renal disease. Here, we investigate the potential effects of long-term human stem cell treatment on kidney function and the gene expression profile of PKD/Mhm (Cy/+) rats. Human adipose-derived stromal cells (ASC) and human skin-derived ABCB5+ stromal cells (2 × 106) were infused intravenously or intraperitoneally monthly, over 6 months. Additionally, ASC and ABCB5+-derived conditioned media were administrated intraperitoneally. The gene expression profile results showed a significant reprogramming of metabolism-related pathways along with downregulation of the cAMP, NF-kB and apoptosis pathways. During the experimental period, we measured the principal renal parameters as well as renal function using an innovative non-invasive transcutaneous device. All together, these analyses show a moderate amelioration of renal function in the ABCB5+ and ASC-treated groups. Additionally, ABCB5+ and ASC-derived conditioned media treatments lead to milder but still promising improvements. Even though further analyses have to be performed, the preliminary results obtained in this study can lay the foundations for a novel therapeutic approach with the application of cell-based therapy in CKD.
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Affiliation(s)
- Daniela Nardozi
- Medical Research Center, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer, 68167 Mannheim, Germany; (D.N.); (S.P.); (A.u.M.K.); (C.S.)
- Vascular Surgery, University Hospital Mannheim, 68167 Mannheim, Germany;
| | - Stefania Palumbo
- Medical Research Center, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer, 68167 Mannheim, Germany; (D.N.); (S.P.); (A.u.M.K.); (C.S.)
| | - Arif ul Maula Khan
- Medical Research Center, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer, 68167 Mannheim, Germany; (D.N.); (S.P.); (A.u.M.K.); (C.S.)
| | - Carsten Sticht
- Medical Research Center, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer, 68167 Mannheim, Germany; (D.N.); (S.P.); (A.u.M.K.); (C.S.)
| | - Karen Bieback
- Institute of Transfusion Medicine and Immunology, Mannheim Institute of Innate Immunoscience, German Red Cross Blood Service Baden-Württemberg—Hessen, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany;
| | - Samar Sadeghi
- RHEACELL GmbH & Co.KG/TICEBA GmbH, 69120 Heidelberg, Germany; (S.S.); (M.A.K.)
| | - Mark Andreas Kluth
- RHEACELL GmbH & Co.KG/TICEBA GmbH, 69120 Heidelberg, Germany; (S.S.); (M.A.K.)
| | - Michael Keese
- Vascular Surgery, University Hospital Mannheim, 68167 Mannheim, Germany;
| | - Norbert Gretz
- Medical Research Center, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer, 68167 Mannheim, Germany; (D.N.); (S.P.); (A.u.M.K.); (C.S.)
- Correspondence:
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8
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Mi Z, Song Y, Wang J, Liu Z, Cao X, Dang L, Lu Y, Sun Y, Xiong H, Zhang L, Chen Y. cAMP-Induced Nuclear Condensation of CRTC2 Promotes Transcription Elongation and Cystogenesis in Autosomal Dominant Polycystic Kidney Disease. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2104578. [PMID: 35037420 PMCID: PMC8981427 DOI: 10.1002/advs.202104578] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 12/03/2021] [Indexed: 06/14/2023]
Abstract
Formation of biomolecular condensates by phase separation has recently emerged as a new principle for regulating gene expression in response to extracellular signaling. However, the molecular mechanisms underlying the coupling of signal transduction and gene activation through condensate formation, and how dysregulation of these mechanisms contributes to disease progression, remain elusive. Here, the authors report that CREB-regulated transcription coactivator 2 (CRTC2) translocates to the nucleus and forms phase-separated condensates upon activation of cAMP signaling. They show that intranuclear CRTC2 interacts with positive transcription elongation factor b (P-TEFb) and activates P-TEFb by disrupting the inhibitory 7SK snRNP complex. Aberrantly elevated cAMP signaling plays central roles in the development of autosomal dominant polycystic kidney disease (ADPKD). They find that CRTC2 localizes to the nucleus and forms condensates in cystic epithelial cells of both mouse and human ADPKD kidneys. Genetic depletion of CRTC2 suppresses cyst growth in an orthologous ADPKD mouse model. Using integrative transcriptomic and cistromic analyses, they identify CRTC2-regulated cystogenesis-associated genes, whose activation depends on CRTC2 condensate-facilitated P-TEFb recruitment and the release of paused RNA polymerase II. Together, their findings elucidate a mechanism by which CRTC2 nuclear condensation conveys cAMP signaling to transcription elongation activation and thereby promotes cystogenesis in ADPKD.
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Affiliation(s)
- Zeyun Mi
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education)The Province and Ministry Co‐sponsored Collaborative Innovation Center for Medical EpigeneticsDepartment of Biochemistry and Molecular BiologySchool of Basic Medical SciencesTianjin Institute of UrologyThe Second Hospital of Tianjin Medical UniversityTianjin Medical UniversityTianjin300070China
| | - Yandong Song
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education)The Province and Ministry Co‐sponsored Collaborative Innovation Center for Medical EpigeneticsDepartment of Biochemistry and Molecular BiologySchool of Basic Medical SciencesTianjin Institute of UrologyThe Second Hospital of Tianjin Medical UniversityTianjin Medical UniversityTianjin300070China
| | - Jiuchen Wang
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education)The Province and Ministry Co‐sponsored Collaborative Innovation Center for Medical EpigeneticsDepartment of Biochemistry and Molecular BiologySchool of Basic Medical SciencesTianjin Institute of UrologyThe Second Hospital of Tianjin Medical UniversityTianjin Medical UniversityTianjin300070China
| | - Zhiheng Liu
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education)The Province and Ministry Co‐sponsored Collaborative Innovation Center for Medical EpigeneticsDepartment of Biochemistry and Molecular BiologySchool of Basic Medical SciencesTianjin Institute of UrologyThe Second Hospital of Tianjin Medical UniversityTianjin Medical UniversityTianjin300070China
| | - Xinyi Cao
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education)The Province and Ministry Co‐sponsored Collaborative Innovation Center for Medical EpigeneticsDepartment of Biochemistry and Molecular BiologySchool of Basic Medical SciencesTianjin Institute of UrologyThe Second Hospital of Tianjin Medical UniversityTianjin Medical UniversityTianjin300070China
| | - Lin Dang
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education)The Province and Ministry Co‐sponsored Collaborative Innovation Center for Medical EpigeneticsDepartment of Biochemistry and Molecular BiologySchool of Basic Medical SciencesTianjin Institute of UrologyThe Second Hospital of Tianjin Medical UniversityTianjin Medical UniversityTianjin300070China
| | - Yumei Lu
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education)The Province and Ministry Co‐sponsored Collaborative Innovation Center for Medical EpigeneticsDepartment of Biochemistry and Molecular BiologySchool of Basic Medical SciencesTianjin Institute of UrologyThe Second Hospital of Tianjin Medical UniversityTianjin Medical UniversityTianjin300070China
| | - Yongzhan Sun
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education)The Province and Ministry Co‐sponsored Collaborative Innovation Center for Medical EpigeneticsDepartment of Biochemistry and Molecular BiologySchool of Basic Medical SciencesTianjin Institute of UrologyThe Second Hospital of Tianjin Medical UniversityTianjin Medical UniversityTianjin300070China
| | - Hui Xiong
- Department of UrologyShandong Provincial Hospital Affiliated to Shandong First Medical UniversityJinanShandong250001China
| | - Lirong Zhang
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education)The Province and Ministry Co‐sponsored Collaborative Innovation Center for Medical EpigeneticsDepartment of Biochemistry and Molecular BiologySchool of Basic Medical SciencesTianjin Institute of UrologyThe Second Hospital of Tianjin Medical UniversityTianjin Medical UniversityTianjin300070China
| | - Yupeng Chen
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education)The Province and Ministry Co‐sponsored Collaborative Innovation Center for Medical EpigeneticsDepartment of Biochemistry and Molecular BiologySchool of Basic Medical SciencesTianjin Institute of UrologyThe Second Hospital of Tianjin Medical UniversityTianjin Medical UniversityTianjin300070China
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Bradford STJ, Grimley E, Laszczyk AM, Lee PH, Patel SR, Dressler GR. Identification of Pax protein inhibitors that suppress target gene expression and cancer cell proliferation. Cell Chem Biol 2022; 29:412-422.e4. [PMID: 34822752 PMCID: PMC8934255 DOI: 10.1016/j.chembiol.2021.11.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 08/24/2021] [Accepted: 11/02/2021] [Indexed: 11/16/2022]
Abstract
The Pax family of developmental control genes are frequently deregulated in human disease. In the kidney, Pax2 is expressed in developing nephrons but not in adult proximal and distal tubules, whereas polycystic kidney epithelia or renal cell carcinoma continues to express high levels. Pax2 reduction in mice or cell culture can slow proliferation of cystic epithelial cells or renal cancer cells. Thus, inhibition of Pax activity may be a viable, cell-type-specific therapy. We designed an unbiased, cell-based, high-throughput screen that identified triazolo pyrimidine derivatives that attenuate Pax transactivation ability. We show that BG-1 inhibits Pax2-positive cancer cell growth and target gene expression but has little effect on Pax2-negative cells. Chromatin immunoprecipitation suggests that these inhibitors prevent Pax protein interactions with the histone H3K4 methylation complex at Pax target genes in renal cells. Thus, these compounds may provide structural scaffolds for kidney-specific inhibitors with therapeutic potential.
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Affiliation(s)
- Shayna T J Bradford
- Department of Pathology, University of Michigan, BSRB 2049, 109 Zina Pitcher Drive, Ann Arbor, MI 48109, USA; Molecular and Cellular Pathology Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA
| | - Edward Grimley
- Department of Pathology, University of Michigan, BSRB 2049, 109 Zina Pitcher Drive, Ann Arbor, MI 48109, USA; Molecular and Cellular Pathology Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA
| | - Ann M Laszczyk
- Department of Pathology, University of Michigan, BSRB 2049, 109 Zina Pitcher Drive, Ann Arbor, MI 48109, USA
| | - Pil H Lee
- Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Sanjeevkumar R Patel
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
| | - Gregory R Dressler
- Department of Pathology, University of Michigan, BSRB 2049, 109 Zina Pitcher Drive, Ann Arbor, MI 48109, USA.
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Lee K, Gusella GL, He JC. Epithelial proliferation and cell cycle dysregulation in kidney injury and disease. Kidney Int 2021; 100:67-78. [PMID: 33831367 PMCID: PMC8855879 DOI: 10.1016/j.kint.2021.03.024] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 03/05/2021] [Accepted: 03/11/2021] [Indexed: 02/08/2023]
Abstract
Various cellular insults and injury to renal epithelial cells stimulate repair mechanisms to adapt and restore the organ homeostasis. Renal tubular epithelial cells are endowed with regenerative capacity, which allows for a restoration of nephron function after acute kidney injury. However, recent evidence indicates that the repair is often incomplete, leading to maladaptive responses that promote the progression to chronic kidney disease. The dysregulated cell cycle and proliferation is also a key feature of renal tubular epithelial cells in polycystic kidney disease and HIV-associated nephropathy. Therefore, in this review, we provide an overview of cell cycle regulation and the consequences of dysregulated cell proliferation in acute kidney injury, polycystic kidney disease, and HIV-associated nephropathy. An increased understanding of these processes may help define better targets for kidney repair and combat chronic kidney disease progression.
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Affiliation(s)
- Kyung Lee
- Department of Medicine, Nephrology Division, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
| | - G Luca Gusella
- Department of Medicine, Nephrology Division, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - John Cijiang He
- Department of Medicine, Nephrology Division, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Renal Program, James J. Peters Veterans Affairs Medical Center, Bronx, New York, USA.
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11
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Yang L, Gu J, Niu X. Complex renal cysts combined with hemorrhage during crizotinib treatment for ALK-rearranged lung adenocarcinoma. Cancer Treat Res Commun 2021; 27:100373. [PMID: 33865115 DOI: 10.1016/j.ctarc.2021.100373] [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: 01/25/2021] [Revised: 03/28/2021] [Accepted: 04/07/2021] [Indexed: 06/12/2023]
Abstract
The oral small-molecule tyrosine kinase inhibitor (TKI), crizotinib has been approved as a first-generation anaplastic lymphoma kinase (ALK) inhibitor in treatment of advanced ALK-positive non-small cell lung cancer (NSCLC). Recently, development of complex renal cysts has been reported with crizotinib usage, highlighting the importance of accurate differentiation between complex renal cysts and new metastasis in NSCLC. Here we describe a case study with confirmed EGFR wild-type and ALK-rearranged lung adenocarcinoma who developed complex renal cysts combined with hemorrhage during crizotinib treatment, with no abnormal clinical symptoms or kidney functions observed. Interestingly, without crizotinib treatment termination or reduction, the complex hemorrhagic renal cysts regressed with self-limiting and healing. The combined usage of ultrasound, CT and MRI techniques in the presented case allowed proper monitoring of the internal changes within complex renal cysts. The patient provided written informed consent authorizing publication of clinical case. Thus, better understanding of the imaging features of crizotinib-related renal cysts combined with hemorrhage would avoid misdiagnoses as a new metastatic renal mass or the aggravation of the primary disease, therefore avoiding further invasive investigation.
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Affiliation(s)
- Ling Yang
- Department of Ultrasonography, Shanghai Chest Hospital, Shanghai Jiao Tong University, Xuhui District, West Huaihai Road No. 241, Shanghai, China
| | - Jianing Gu
- Department of Cardiology, Shanghai Fifth People's Hospital, Fudan University, Minhang District, Heqing Road No. 801, Shanghai, China
| | - Xiaomin Niu
- Department of Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Xuhui District, West Huaihai Road No. 241, Shanghai, China.
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12
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Shao L, El-Jouni W, Kong F, Ramesh J, Kumar RS, Shen X, Ren J, Devendra S, Dorschel A, Wu M, Barrera I, Tabari A, Hu K, Haque N, Yambayev I, Li S, Kumar A, Behera TR, McDonough G, Furuichi M, Xifaras M, Lu T, Alhayaza RM, Miyabayashi K, Fan Q, Ajay AK, Zhou J. Genetic reduction of cilium length by targeting intraflagellar transport 88 protein impedes kidney and liver cyst formation in mouse models of autosomal polycystic kidney disease. Kidney Int 2020; 98:1225-1241. [DOI: 10.1016/j.kint.2020.05.049] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 05/23/2020] [Accepted: 05/28/2020] [Indexed: 12/31/2022]
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13
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Yuan X, He F, Zheng F, Xu Y, Zou J. Interferon-gamma Facilitates Neurogenesis by Activating Wnt/β-catenin Cell Signaling Pathway via Promotion of STAT1 Regulation of the β-Catenin Promoter. Neuroscience 2020; 448:219-233. [PMID: 32860934 DOI: 10.1016/j.neuroscience.2020.08.018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 08/12/2020] [Accepted: 08/13/2020] [Indexed: 01/27/2023]
Abstract
Interferon-gamma (IFN-γ) is critical for central nervous system (CNS) functions and it may be a promising treatment to stimulate CNS regeneration. However, previous studies reported inconsistent results, and the molecular mechanisms remain controversial. Here we show that IFN-γ-treated mice via intraperitoneal injection have elevated IFN-γ level in central hippocampus and superior cognitive behaviors IFN-γ could activates the level of protein expression of Wnt7a, β-catenin, and CyclinD1 in Wnt/β-catenin signaling pathway of mice hippocampus. Functional and mechanism analysis in vitro revealed that IFN-γ promoted the proliferation and differentiation in primary cultured neural stem cells (NSCs). STAT1 was accountable for IFN-γ-induced activation of the β-catenin promoter, and IFN-γ increased the binding affinity of STAT1 to β-catenin promoter based on luciferase activity and chromatin immunoprecipitation. Our results suggest that IFN-γ exerts many effects ranging from cognitive function in vivo to NSC proliferation, self-renewal, and differentiation in vitro. It does so by recruiting STAT1 to the β-catenin promoter, enhancing cis-regulation by STAT1, and ultimately activating Wnt/β-catenin signaling. In this study, we first found that STAT1 was recruited into the promoter of β-catenin to activate β-catenin expression, and this effect was regulated by IFN-γ. It is also discovered firstly that Wnt/β-catenin and JAK/STAT pathways form cross-links through STAT1. Promoting neurogenesis through immune stimulation might be a promising strategy for repairing the diseased/injured CNS. This study provides a scientific basis for immunomodulation to promote nerve regeneration and offer a new therapeutic direction for central nervous system regeneration.
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Affiliation(s)
- Xianlin Yuan
- Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
| | - Fen He
- Department of Radiation Oncology, First Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Fuxiang Zheng
- Institute of Human Virology and Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Yunlong Xu
- Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
| | - Juntao Zou
- Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China.
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14
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Ikeda K, Kusaba T, Tomita A, Watanabe-Uehara N, Ida T, Kitani T, Yamashita N, Uehara M, Matoba S, Yamada T, Tamagaki K. Diverse Receptor Tyrosine Kinase Phosphorylation in Urine-Derived Tubular Epithelial Cells from Autosomal Dominant Polycystic Kidney Disease Patients. Nephron Clin Pract 2020; 144:525-536. [PMID: 32799196 DOI: 10.1159/000509419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 06/12/2020] [Indexed: 11/19/2022] Open
Abstract
BACKGROUNDS The clinical features of autosomal dominant polycystic kidney disease (ADPKD) differ among patients even if they have the same gene mutation in PKD1 or PKD2. This suggests that there is diversity in the expression of other modifier genes or in the underlying molecular mechanisms of ADPKD, but these are not well understood. METHODS We primarily cultured solute carrier family 12 member 3 (SLC12A3)-positive urine-derived distal tubular epithelial cells from 6 ADPKD patients and 4 healthy volunteers and established immortalized cell lines. The diversity in receptor tyrosine kinase (RTK) phosphorylation by phospho-RTK array in immortalized tubular epithelial cells was analyzed. RESULTS We noted diversity in the activation of several molecules, including Met, a receptor of hepatocyte growth factor (HGF). Administration of golvatinib, a selective Met inhibitor, or transfection of small interfering RNA for Met suppressed cell proliferation and downstream signaling only in the cell lines in which hyperphosphorylation of Met was observed. In three-dimensional culture of Madin-Darby canine kidney (MDCK) cells as a cyst formation model of ADPKD, HGF activated Met, resulting in an increased total cyst number and total cyst volume. Administration of golvatinib inhibited these phenotypes in MDCK cells. CONCLUSION Analysis of urine-derived tubular epithelial cells demonstrated diverse RTK phosphorylation in ADPKD, and Met phosphorylation was noted in some patients. Considering the difference in the effects of golvatinib on immortalized tubular epithelial cells among patients, this analysis may aid in selecting suitable drugs for individual ADPKD patients.
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Affiliation(s)
- Kisho Ikeda
- Department of Nephrology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Tetsuro Kusaba
- Department of Nephrology, Kyoto Prefectural University of Medicine, Kyoto, Japan,
| | - Aya Tomita
- Department of Nephrology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | | | - Tomoharu Ida
- Department of Nephrology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Takashi Kitani
- Department of Nephrology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Noriyuki Yamashita
- Department of Nephrology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Masahiro Uehara
- Department of Nephrology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Satoaki Matoba
- Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Tadaaki Yamada
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Keiichi Tamagaki
- Department of Nephrology, Kyoto Prefectural University of Medicine, Kyoto, Japan
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15
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Molecular pathways involved in injury-repair and ADPKD progression. Cell Signal 2020; 72:109648. [PMID: 32320858 DOI: 10.1016/j.cellsig.2020.109648] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 04/16/2020] [Accepted: 04/17/2020] [Indexed: 12/29/2022]
Abstract
The major hallmark of Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the formation of many fluid-filled cysts in the kidneys, which ultimately impairs the normal renal structure and function, leading to end-stage renal disease (ESRD). A large body of evidence suggests that injury-repair mechanisms are part of ADPKD progression. Once cysts have been formed, proliferation and fluid secretion contribute to the cyst size increase, which eventually causes stress on the surrounding tissue resulting in local injury and fibrosis. In addition, renal injury can cause or accelerate cyst formation. In this review, we will describe the various mechanisms activated during renal injury and tissue repair and show how they largely overlap with the molecular mechanisms activated during PKD progression. In particular, we will discuss molecular mechanisms such as proliferation, inflammation, cell differentiation, cytokines and growth factors secretion, which are activated following the renal injury to allow the remodelling of the tissue and a proper organ repair. We will also underline how, in a context of PKD-related gene mutations, aberrant or chronic activation of these developmental pathways and repair/remodelling mechanisms results in exacerbation of the disease.
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16
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Chen YC, Su YC, Shieh GS, Su BH, Su WC, Huang PH, Jiang ST, Shiau AL, Wu CL. Prothymosin α promotes STAT3 acetylation to induce cystogenesis in Pkd1-deficient mice. FASEB J 2019; 33:13051-13061. [PMID: 31589480 DOI: 10.1096/fj.201900504r] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Polycystic kidney disease (PKD) is characterized by the expansion of fluid-filled cysts in the kidney, which impair the function of kidney and eventually leads to end-stage renal failure. It has been previously demonstrated that transgenic overexpression of prothymosin α (ProT) induces the development of PKD; however, the underlying mechanisms remain unclear. In this study, we used a mouse PKD model that sustains kidney-specific low-expression of Pkd1 to illustrate that aberrant up-regulation of ProT occurs in cyst-lining epithelial cells, and we further developed an in vitro cystogenesis model to demonstrate that the suppression of ProT is sufficient to reduce cyst formation. Next, we found that the expression of ProT was accompanied with prominent augmentation of protein acetylation in PKD, which results in the activation of downstream signal transducer and activator of transcription (STAT) 3. The pathologic role of STAT3 in PKD has been previously reported. We determined that this molecular mechanism of protein acetylation is involved with the interaction between ProT and STAT3; consequently, it causes the deprivation of histone deacetylase 3 from the indicated protein. Conclusively, these results elucidate the significant role of ProT, including protein acetylation and STAT3 activation in PKD, which represent potential for ameliorating the disease progression of PKD.-Chen, Y.-C., Su, Y.-C., Shieh, G.-S., Su, B.-H., Su, W.-C., Huang, P.-H., Jiang, S.-T., Shiau, A.-L., Wu, C.-L. Prothymosin α promotes STAT3 acetylation to induce cystogenesis in Pkd1-deficient mice.
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Affiliation(s)
- Yi-Cheng Chen
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yu-Chu Su
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Department of Otolaryngology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Gia-Shing Shieh
- Department of Urology, Tainan Hospital, Ministry of Health and Welfare, Executive Yuan, Tainan, Taiwan
| | - Bing-Hua Su
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Wen-Cheng Su
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Pei-Hsin Huang
- Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan
| | - Si-Tse Jiang
- National Laboratory Animal Center, National Applied Research Laboratories, Taipei, Taiwan
| | - Ai-Li Shiau
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chao-Liang Wu
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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17
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Xue C, Mei CL. Polycystic Kidney Disease and Renal Fibrosis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1165:81-100. [PMID: 31399962 DOI: 10.1007/978-981-13-8871-2_5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Polycystic kidney disease (PKD) is a common genetic disorder characterized by formations of numerous cysts in kidneys and most caused by PKD1 or PKD2 mutations in autosomal dominant polycystic kidney disease (ADPKD). The interstitial inflammation and fibrosis is one of the major pathological changes in polycystic kidney tissues with an accumulation of inflammatory cells, chemokines, and cytokines. The immune response is observed across different stages and occurs prior to or coincident with cyst formation in ADPKD. Evidence for inflammation as an important contributor to cyst growth and fibrosis includes increased interstitial macrophages, upregulated expressions of pro-inflammatory cytokines, activated complement system, and activated pathways including NF-κB and JAK-STAT signaling in polycystic kidney tissues. Inflammatory cells are responsible for overproduction of several pro-fibrotic growth factors which promote renal fibrosis in ADPKD. These growth factors trigger epithelial mesenchymal transition and myofibroblast/fibrocyte activation, which stimulate the expansion of extracellular matrix (ECM) including collagen I, III, IV, V, and fibronectin, leading to renal fibrosis and reduced renal function. Besides, there are imbalanced ECM turnover regulators which lead to the increased ECM production and inadequate degradation in polycystic kidney tissues. Several fibrosis associated signaling pathways, such as TGFβ-SMAD, Wnt, and periostin-integrin-linked kinase are also activated in polycystic kidney tissues. Although the effective anti-fibrotic treatments are limited at the present time, slowing the cyst expansion and fibrosis development is very important for prolonging life span and improving the palliative care of ADPKD patients. The inhibition of pro-fibrotic cytokines involved in fibrosis might be a new therapeutic strategy for ADPKD in the future.
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Affiliation(s)
- Cheng Xue
- Division of Nephrology, Kidney Institute of PLA, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Chang-Lin Mei
- Division of Nephrology, Kidney Institute of PLA, Changzheng Hospital, Second Military Medical University, Shanghai, China.
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18
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Malekshahabi T, Khoshdel Rad N, Serra AL, Moghadasali R. Autosomal dominant polycystic kidney disease: Disrupted pathways and potential therapeutic interventions. J Cell Physiol 2019; 234:12451-12470. [PMID: 30644092 DOI: 10.1002/jcp.28094] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Accepted: 12/07/2018] [Indexed: 12/18/2022]
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is a monogenic inherited renal cystic disease that occurs in different races worldwide. It is characterized by the development of a multitude of renal cysts, which leads to massive enlargement of the kidney and often to renal failure in adulthood. ADPKD is caused by a mutation in PKD1 or PKD2 genes encoding the proteins polycystin-1 and polycystin-2, respectively. Recent studies showed that cyst formation and growth result from deregulation of multiple cellular pathways like proliferation, apoptosis, metabolic processes, cell polarity, and immune defense. In ADPKD, intracellular cyclic adenosine monophosphate (cAMP) promotes cyst enlargement by stimulating cell proliferation and transepithelial fluid secretion. Several interventions affecting many of these defective signaling pathways have been effective in animal models and some are currently being tested in clinical trials. Moreover, the stem cell therapy can improve nephropathies and according to studies were done in this field, can be considered as a hopeful therapeutic approach in future for PKD. This study provides an in-depth review of the relevant molecular pathways associated with the pathogenesis of ADPKD and their implications in development of potential therapeutic strategies.
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Affiliation(s)
- Talieh Malekshahabi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Niloofar Khoshdel Rad
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Andreas L Serra
- Department of Internal Medicine and Nephrology, Klinik Hirslanden, Zurich, Switzerland
| | - Reza Moghadasali
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
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19
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de Stephanis L, Mangolini A, Servello M, Harris PC, Dell'Atti L, Pinton P, Aguiari G. MicroRNA501-5p induces p53 proteasome degradation through the activation of the mTOR/MDM2 pathway in ADPKD cells. J Cell Physiol 2018; 233:6911-6924. [PMID: 29323708 DOI: 10.1002/jcp.26473] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Accepted: 01/05/2018] [Indexed: 01/01/2023]
Abstract
Cell proliferation and apoptosis are typical hallmarks of autosomal dominant polycystic kidney disease (ADPKD) and cause the development of kidney cysts that lead to end-stage renal disease (ESRD). Many factors, impaired by polycystin complex loss of function, may promote these biological processes, including cAMP, mTOR, and EGFR signaling pathways. In addition, microRNAs (miRs) may also regulate the ADPKD related signaling network and their dysregulation contributes to disease progression. However, the role of miRs in ADPKD pathogenesis has not been fully understood, but also the function of p53 is quite obscure, especially its regulatory contribution on cell proliferation and apoptosis. Here, we describe for the first time that miR501-5p, upregulated in ADPKD cells and tissues, induces the activation of mTOR kinase by PTEN and TSC1 gene repression. The increased activity of mTOR kinase enhances the expression of E3 ubiquitin ligase MDM2 that in turn promotes p53 ubiquitination, leading to its degradation by proteasome machinery in a network involving p70S6K. Moreover, the overexpression of miR501-5p stimulates cell proliferation in kidney cells by the inhibition of p53 function in a mechanism driven by mTOR signaling. In fact, the downregulation of this miR as well as the pharmacological treatment with proteasome and mTOR inhibitors in ADPKD cells reduces cell growth by the activation of apoptosis. Consequently, the stimulation of cell death in ADPKD cells may occur through the inhibition of mTOR/MDM2 signaling and the restoring of p53 function. The data presented here confirm that the impaired mTOR signaling plays an important role in ADPKD.
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Affiliation(s)
- Lucia de Stephanis
- Department of Biomedical and Surgical Specialty Sciences, University of Ferrara, Ferrara, Italy
| | | | - Miriam Servello
- Department of Biomedical and Surgical Specialty Sciences, University of Ferrara, Ferrara, Italy.,Unit of Urology, St. Anna Hospital, Ferrara, Italy
| | - Peter C Harris
- Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota
| | | | - Paolo Pinton
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Gianluca Aguiari
- Department of Biomedical and Surgical Specialty Sciences, University of Ferrara, Ferrara, Italy
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20
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Li A, Xu Y, Fan S, Meng J, Shen X, Xiao Q, Li Y, Zhang L, Zhang X, Wu G, Liang C, Wu D. Canonical Wnt inhibitors ameliorate cystogenesis in a mouse ortholog of human ADPKD. JCI Insight 2018. [PMID: 29515026 DOI: 10.1172/jci.insight.95874] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) can be caused by mutations in the PKD1 or PKD2 genes. The PKD1 gene product is a Wnt cell-surface receptor. We previously showed that a lack of the PKD2 gene product, PC2, increases β-catenin signaling in mouse embryonic fibroblasts, kidney renal epithelia, and isolated renal collecting duct cells. However, it remains unclear whether β-catenin signaling plays a role in polycystic kidney disease phenotypes or if a Wnt inhibitor can halt cyst formation in ADPKD disease models. Here, using genetic and pharmacologic approaches, we demonstrated that the elevated β-catenin signaling caused by PC2 deficiency contributes significantly to disease phenotypes in a mouse ortholog of human ADPKD. Pharmacologically inhibiting β-catenin stability or the production of mature Wnt protein, or genetically reducing the expression of Ctnnb1 (which encodes β-catenin), suppressed the formation of renal cysts, improved renal function, and extended survival in ADPKD mice. Our study clearly demonstrates the importance of β-catenin signaling in disease phenotypes associated with Pkd2 mutation. It also describes the effects of two Wnt inhibitors, XAV939 and LGK974, on various Wnt signaling targets as a potential therapeutic modality for ADPKD, for which there is currently no effective therapy.
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Affiliation(s)
- Ao Li
- Anhui Province PKD Center, Institute and Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China.,Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Yuchen Xu
- Anhui Province PKD Center, Institute and Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
| | - Song Fan
- Anhui Province PKD Center, Institute and Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
| | - Jialin Meng
- Anhui Province PKD Center, Institute and Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
| | - Xufeng Shen
- Anhui Province PKD Center, Institute and Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
| | - Qian Xiao
- Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Yuan Li
- State Key Laboratory of Molecular Oncology, Cancer Hospital and Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Li Zhang
- Anhui Province PKD Center, Institute and Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
| | - Xiansheng Zhang
- Anhui Province PKD Center, Institute and Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
| | - Guanqing Wu
- Anhui Province PKD Center, Institute and Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China.,State Key Laboratory of Molecular Oncology, Cancer Hospital and Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chaozhao Liang
- Anhui Province PKD Center, Institute and Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
| | - Dianqing Wu
- Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA
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21
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Puri P, Schaefer CM, Bushnell D, Taglienti ME, Kreidberg JA, Yoder BK, Bates CM. Ectopic Phosphorylated Creb Marks Dedifferentiated Proximal Tubules in Cystic Kidney Disease. THE AMERICAN JOURNAL OF PATHOLOGY 2018; 188:84-94. [PMID: 29107072 PMCID: PMC5745541 DOI: 10.1016/j.ajpath.2017.09.015] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Revised: 08/18/2017] [Accepted: 09/11/2017] [Indexed: 01/25/2023]
Abstract
Ectopic cAMP signaling is pathologic in polycystic kidney disease; however, its spatiotemporal actions are unclear. We characterized the expression of phosphorylated Creb (p-Creb), a target and mediator of cAMP signaling, in developing and cystic kidney models. We also examined tubule-specific effects of cAMP analogs in cystogenesis in embryonic kidney explants. In wild-type mice, p-Creb marked nephron progenitors (NP), early epithelial NP derivatives, ureteric bud, and cortical stroma; p-Creb was present in differentiated thick ascending limb of Henle, collecting duct, and stroma; however, it disappeared in mature NP-derived proximal tubules. In Six2cre;Frs2αFl/Fl mice, a renal cystic model, ectopic p-Creb stained proximal tubule-derived cystic segments that lost the differentiation marker lotus tetragonolobus lectin. Furthermore, lotus tetragonolobus lectin-negative/p-Creb-positive cyst segments (re)-expressed Ncam1, Pax2, and Sox9 markers of immature nephron structures and dedifferentiated proximal tubules after acute kidney injury. These dedifferentiation markers were co-expressed with p-Creb in renal cysts in Itf88 knockout mice subjected to ischemia and Six2cre;Pkd1Fl/Fl mice, other renal cystogenesis models. 8-Br-cAMP addition to wild-type embryonic kidney explants induced proximal tubular cystogenesis and p-Creb expression; these effects were blocked by co-addition of protein kinase A inhibitor. Thus p-Creb/cAMP signaling is appropriate in NP and early nephron derivatives, but disappears in mature proximal tubules. Moreover, ectopic p-Creb expression/cAMP signaling marks dedifferentiated proximal tubular cystic segments. Furthermore, proximal tubules are predisposed to become cystic after cAMP stimulation.
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Affiliation(s)
- Pawan Puri
- Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
| | - Caitlin M Schaefer
- Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Daniel Bushnell
- Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Mary E Taglienti
- Department of Urology, Boston Children's Hospital, Boston, Massachusetts; Department of Surgery, Harvard Medical School, Boston, Massachusetts
| | - Jordan A Kreidberg
- Department of Urology, Boston Children's Hospital, Boston, Massachusetts; Department of Surgery, Harvard Medical School, Boston, Massachusetts
| | - Bradley K Yoder
- Department of Pediatrics, Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Carlton M Bates
- Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Division of Nephrology, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
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22
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Song CJ, Zimmerman KA, Henke SJ, Yoder BK. Inflammation and Fibrosis in Polycystic Kidney Disease. Results Probl Cell Differ 2017; 60:323-344. [PMID: 28409351 PMCID: PMC7875307 DOI: 10.1007/978-3-319-51436-9_12] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Polycystic kidney disease (PKD) is a commonly inherited disorder characterized by cyst formation and fibrosis (Wilson, N Engl J Med 350:151-164, 2004) and is caused by mutations in cilia or cilia-related proteins, such as polycystin 1 or 2 (Oh and Katsanis, Development 139:443-448, 2012; Kotsis et al., Nephrol Dial Transplant 28:518-526, 2013). A major pathological feature of PKD is the development of interstitial inflammation and fibrosis with an associated accumulation of inflammatory cells (Grantham, N Engl J Med 359:1477-1485, 2008; Zeier et al., Kidney Int 42:1259-1265, 1992; Ibrahim, Sci World J 7:1757-1767, 2007). It is unclear whether inflammation is a driving force for cyst formation or a consequence of the pathology (Ta et al., Nephrology 18:317-330, 2013) as in some murine models cysts are present prior to the increase in inflammatory cells (Phillips et al., Kidney Blood Press Res 30:129-144, 2007; Takahashi et al., J Am Soc Nephrol JASN 1:980-989, 1991), while in other models the increase in inflammatory cells is present prior to or coincident with cyst initiation (Cowley et al., Kidney Int 43:522-534, 1993, Kidney Int 60:2087-2096, 2001). Additional support for inflammation as an important contributor to cystic kidney disease is the increased expression of many pro-inflammatory cytokines in murine models and human patients with cystic kidney disease (Karihaloo et al., J Am Soc Nephrol JASN 22:1809-1814, 2011; Swenson-Fields et al., Kidney Int, 2013; Li et al., Nat Med 14:863-868, 2008a). Based on these data, an emerging model in the field is that disruption of primary cilia on tubule epithelial cells leads to abnormal cytokine cross talk between the epithelium and the inflammatory cells contributing to cyst growth and fibrosis (Ta et al., Nephrology 18:317-330, 2013). These cytokines are produced by interstitial fibroblasts, inflammatory cells, and tubule epithelial cells and activate multiple pathways including the JAK-STAT and NF-κB signaling (Qin et al., J Am Soc Nephrol JASN 23:1309-1318, 2012; Park et al., Am J Nephrol 32:169-178, 2010; Bhunia et al., Cell 109:157-168, 2002). Indeed, inflammatory cells are responsible for producing several of the pro-fibrotic growth factors observed in PKD patients with fibrosis (Nakamura et al., Am J Nephrol 20:32-36, 2000; Wilson et al., J Cell Physiol 150:360-369, 1992; Song et al., Hum Mol Genet 18:2328-2343, 2009; Schieren et al., Nephrol Dial Transplant 21:1816-1824, 2006). These growth factors trigger epithelial cell proliferation and myofibroblast activation that stimulate the production of extracellular matrix (ECM) genes including collagen types 1 and 3 and fibronectin, leading to reduced glomerular function with approximately 50% of ADPKD patients progressing to end-stage renal disease (ESRD). Therefore, treatments designed to reduce inflammation and slow the rate of fibrosis are becoming important targets that hold promise to improve patient life span and quality of life. In fact, recent studies in several PKD mouse models indicate that depletion of macrophages reduces cyst severity. In this chapter, we review the potential mechanisms of interstitial inflammation in PKD with a focus on ADPKD and discuss the role of interstitial inflammation in progression to fibrosis and ESRD.
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Affiliation(s)
- Cheng Jack Song
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Kurt A Zimmerman
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Scott J Henke
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Bradley K Yoder
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA.
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Xiao Q, Chen Z, Jin X, Mao R, Chen Z. The many postures of noncanonical Wnt signaling in development and diseases. Biomed Pharmacother 2017. [PMID: 28651237 DOI: 10.1016/j.biopha.2017.06.061] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Wnt signaling regulates many aspects of vertebrate development. Its dysregulation causes developmental defects and diseases including cancer. The signaling can be categorized in two pathways: canonical and noncanonical. Canonical pathway plays a key role in regulating proliferation and differentiation of cells whilst noncanonical Wnt signaling mainly controls cellular polarity and motility. During development, noncanonical Wnt signaling is required for tissue formation. Recent studies have shown that noncanonical Wnt signaling is involved in adult tissue development and cancer progression. In this review, we try to describe and discuss the mechanisms behind the biological effects of noncanonical Wnt signaling, diseases caused by its dysregulation, and implications in adult tissue development biology.
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Affiliation(s)
- Qian Xiao
- Senior Research Scientist, Department of Pharmacology, School of Medicine, Yale University, New Haven, USA
| | - Zhengxi Chen
- PhD, Department of Orthodontics, Ninth People's Hospital, School of Stomatology, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaozhuang Jin
- PhD, Faculty of Dentistry, The University of Hong Kong, Hong Kong
| | - Runyi Mao
- MDS student, Department of Oral and Maxillofacial Surgery, Ninth People's Hospital, School of Stomatology, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University, Shanghai, China
| | - Zhenqi Chen
- Professor, Department of Orthodontics, Ninth People's Hospital, School of Stomatology, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University, Shanghai, China
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24
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Remodeling the Th1 polarized systemic environment contributes to neurogenesis and cognitive function via the Wnt7a pathway in neonatal mice. Neurobiol Learn Mem 2017; 141:60-71. [DOI: 10.1016/j.nlm.2017.03.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Revised: 02/11/2017] [Accepted: 03/02/2017] [Indexed: 11/17/2022]
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Overexpression of exogenous kidney-specific Ngal attenuates progressive cyst development and prolongs lifespan in a murine model of polycystic kidney disease. Kidney Int 2017; 91:412-422. [DOI: 10.1016/j.kint.2016.09.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Revised: 08/31/2016] [Accepted: 09/01/2016] [Indexed: 11/23/2022]
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Abstract
Primary cilia are small, antenna-like structures that detect mechanical and chemical cues and transduce extracellular signals. While mammalian primary cilia were first reported in the late 1800s, scientific interest in these sensory organelles has burgeoned since the beginning of the twenty-first century with recognition that primary cilia are essential to human health. Among the most common clinical manifestations of ciliary dysfunction are renal cysts. The molecular mechanisms underlying renal cystogenesis are complex, involving multiple aberrant cellular processes and signaling pathways, while initiating molecular events remain undefined. Autosomal Dominant Polycystic Kidney Disease is the most common renal cystic disease, caused by disruption of polycystin-1 and polycystin-2 transmembrane proteins, which evidence suggests must localize to primary cilia for proper function. To understand how the absence of these proteins in primary cilia may be remediated, we review intracellular trafficking of polycystins to the primary cilium. We also examine the controversial mechanisms by which primary cilia transduce flow-mediated mechanical stress into intracellular calcium. Further, to better understand ciliary function in the kidney, we highlight the LKB1/AMPK, Wnt, and Hedgehog developmental signaling pathways mediated by primary cilia and misregulated in renal cystic disease.
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Li Y, Tian X, Ma M, Jerman S, Kong S, Somlo S, Sun Z. Deletion of ADP Ribosylation Factor-Like GTPase 13B Leads to Kidney Cysts. J Am Soc Nephrol 2016; 27:3628-3638. [PMID: 27153923 PMCID: PMC5118478 DOI: 10.1681/asn.2015091004] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2015] [Accepted: 03/08/2016] [Indexed: 12/14/2022] Open
Abstract
The gene for ADP ribosylation factor-like GTPase 13B (Arl13b) encodes a small GTPase essential for cilia biogenesis in multiple model organisms. Inactivation of arl13b in zebrafish leads to a number of phenotypes indicative of defective cilia, including cystic kidneys. In mouse, null mutation in Arl13b results in severe patterning defects in the neural tube and defective Hedgehog signaling. Human mutations of ARL13B lead to Joubert syndrome, a ciliopathy. However, patients with mutated ARL13B do not develop kidney cysts. To investigate whether Arl13b has a role in ciliogenesis in mammalian kidney and whether loss of function of Arl13b leads to cystic kidneys in mammals, we generated a mouse model with kidney-specific conditional knockout of Arl13b Deletion of Arl13b in the distal nephron at the perinatal stage led to a cilia biogenesis defect and rapid kidney cyst formation. Additionally, we detected misregulation of multiple pathways in the cystic kidneys of this model. Moreover, valproic acid, a histone deacetylase inhibitor that we previously showed slows cyst progression in a mouse cystic kidney model with neonatal inactivation of Pkd1, inhibited the early rise of Wnt7a expression, ameliorated fibrosis, slowed cyst progression, and improved kidney function in the Arl13b mutant mouse. Finally, in rescue experiments in zebrafish, all ARL13B allele combinations identified in patients with Joubert syndrome provided residual Arl13b function, supporting the idea that the lack of cystic kidney phenotype in human patients with ARL13B mutations is explained by the hypomorphic nature of the mutations.
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Affiliation(s)
| | - Xin Tian
- Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Ming Ma
- Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | | | | | - Stefan Somlo
- Departments of *Genetics and
- Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
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Izzedine H, El-Fekih RK, Perazella MA. The renal effects of ALK inhibitors. Invest New Drugs 2016; 34:643-9. [PMID: 27468827 DOI: 10.1007/s10637-016-0379-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2016] [Accepted: 07/20/2016] [Indexed: 12/18/2022]
Abstract
Anaplastic lymphoma kinase 1 (ALK-1) is a member of the insulin receptor tyrosine kinase family. In clinical practice, three small molecule inhibitors of ALK-1 are used, namely crizotinib, ceritinib and alectinib. Several more agents are in active pre-clinical and clinical studies. Crizotinib is approved for the treatment of advanced ALK-positive non-small cell lung cancer (NSCLC). According to the package insert and published literature, treatment with crizotinib appears to be associated with kidney failure as well as an increased risk for the development and progression of renal cysts. In addition, this agent is associated with development of peripheral edema and rare electrolyte disorders. This review focuses on the adverse renal effects of Crizotinib in clinical practice.
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Affiliation(s)
- Hassan Izzedine
- Department of Nephrology, Monceau Park International Clinic Paris, Paris, France.
| | | | - Mark A Perazella
- Department of Nephrology, Yale University School of Medicine, New Haven, CT, 06520, USA
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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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Wu M, Gu J, Mei S, Xu D, Jing Y, Yao Q, Chen M, Yang M, Chen S, Yang B, Qi N, Hu H, Wüthrich RP, Mei C. Resveratrol delays polycystic kidney disease progression through attenuation of nuclear factor κB-induced inflammation. Nephrol Dial Transplant 2016; 31:1826-1834. [PMID: 27190325 DOI: 10.1093/ndt/gfw058] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Accepted: 02/24/2016] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Inflammation plays an important role in polycystic kidney disease (PKD). The current study aimed to examine the efficacy of the anti-inflammatory compound resveratrol in PKD and to investigate its underlying mechanism of action. METHODS Male Han:SPRD (Cy/+) rats with PKD were treated with 200 mg/kg/day resveratrol or vehicle by gavage for 5 weeks. Human autosomal dominant (AD) PKD cells, three-dimensional (3D) Madin-Darby canine kidney cells and zebrafish were treated with various concentrations of resveratrol or the nuclear factor κB (NF-κB) inhibitor QNZ. RESULTS Resveratrol treatment reduced blood urea nitrogen levels and creatinine levels by 20 and 24%, respectively, and decreased two-kidney/total body weight ratio by 15% and cyst volume density by 24% in Cy/+ rats. The proliferation index and the macrophage infiltration index were reduced by 40 and 43%, respectively, in resveratrol-treated cystic kidneys. Resveratrol reduced the levels of the pro-inflammatory factors monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α) and complement factor B (CFB) in Cy/+ rat kidneys in parallel with the decreased activity of NF-κB (p50/p65). The activation of NF-κB and its correlation with pro-inflammatory factor expression were confirmed in human ADPKD cells and kidney tissues. Resveratrol and QNZ inhibited the expression of MCP-1, TNF-α and CFB and reduced NF-κB activity in ADPKD cells. Moreover, NF-κB blockage minimized the inhibition of inflammatory factor production by resveratrol treatment. Furthermore, resveratrol or QNZ inhibited cyst formation in the 3D cyst and zebrafish models. CONCLUSIONS The NF-κB signaling pathway is activated and partly responsible for inflammation in polycystic kidney tissues. Targeting inflammation through resveratrol could be a new strategy for PKD treatment in the future.
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Affiliation(s)
- Ming Wu
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Junhui Gu
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Shuqin Mei
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Dechao Xu
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Ying Jing
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Qing Yao
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Meihan Chen
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Ming Yang
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Sixiu Chen
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Bo Yang
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Na Qi
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Huimin Hu
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | | | - Changlin Mei
- Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
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Mohamed TMA, Abou-Leisa R, Stafford N, Maqsood A, Zi M, Prehar S, Baudoin-Stanley F, Wang X, Neyses L, Cartwright EJ, Oceandy D. The plasma membrane calcium ATPase 4 signalling in cardiac fibroblasts mediates cardiomyocyte hypertrophy. Nat Commun 2016; 7:11074. [PMID: 27020607 PMCID: PMC4820544 DOI: 10.1038/ncomms11074] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2015] [Accepted: 02/17/2016] [Indexed: 12/26/2022] Open
Abstract
The heart responds to pathological overload through myocyte hypertrophy. Here we show that this response is regulated by cardiac fibroblasts via a paracrine mechanism involving plasma membrane calcium ATPase 4 (PMCA4). Pmca4 deletion in mice, both systemically and specifically in fibroblasts, reduces the hypertrophic response to pressure overload; however, knocking out Pmca4 specifically in cardiomyocytes does not produce this effect. Mechanistically, cardiac fibroblasts lacking PMCA4 produce higher levels of secreted frizzled related protein 2 (sFRP2), which inhibits the hypertrophic response in neighbouring cardiomyocytes. Furthermore, we show that treatment with the PMCA4 inhibitor aurintricarboxylic acid (ATA) inhibits and reverses cardiac hypertrophy induced by pressure overload in mice. Our results reveal that PMCA4 regulates the development of cardiac hypertrophy and provide proof of principle for a therapeutic approach to treat this condition.
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Affiliation(s)
- Tamer M A Mohamed
- Institute of Cardiovascular Sciences, University of Manchester, AV Hill Building, Manchester M13 9PT, UK.,J David Gladstone Research Institutes, San Francisco, California 94158, USA.,Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt
| | - Riham Abou-Leisa
- Institute of Cardiovascular Sciences, University of Manchester, AV Hill Building, Manchester M13 9PT, UK
| | - Nicholas Stafford
- Institute of Cardiovascular Sciences, University of Manchester, AV Hill Building, Manchester M13 9PT, UK
| | - Arfa Maqsood
- Institute of Cardiovascular Sciences, University of Manchester, AV Hill Building, Manchester M13 9PT, UK
| | - Min Zi
- Institute of Cardiovascular Sciences, University of Manchester, AV Hill Building, Manchester M13 9PT, UK
| | - Sukhpal Prehar
- Institute of Cardiovascular Sciences, University of Manchester, AV Hill Building, Manchester M13 9PT, UK
| | - Florence Baudoin-Stanley
- Institute of Cardiovascular Sciences, University of Manchester, AV Hill Building, Manchester M13 9PT, UK
| | - Xin Wang
- Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK
| | - Ludwig Neyses
- Institute of Cardiovascular Sciences, University of Manchester, AV Hill Building, Manchester M13 9PT, UK
| | - Elizabeth J Cartwright
- Institute of Cardiovascular Sciences, University of Manchester, AV Hill Building, Manchester M13 9PT, UK
| | - Delvac Oceandy
- Institute of Cardiovascular Sciences, University of Manchester, AV Hill Building, Manchester M13 9PT, UK
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Abstract
Diverse signaling pathways have been reported to be associated with polycystic kidney disease (PKD). Cell proliferation is widely known to be an important pathway related to this disease. However, studies on the interactions of inflammation and fibrosis with polycystic kidney disease have been limited. Inflammation is one of the protective systems involved in the response to foreign molecules. In PKD, it was reported that the activity of signaling pathways associated with inflammation is increased. Also, fibrosis is the development of excess fibrous tissue in organ or tissue. It is an abnormal phenomenon in which the extent of fibrous connective tissues is increased. In PKD, increases in the activity of molecules such as growth factor and TGF-β have been reported to occur and promote fibrosis. Therefore, the inflammation and fibrosis responses have been suggested as therapeutic targets for PKD. In order to guide further studies, this review indicates the roles of inflammatory and fibrosis signaling in PKD.
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Affiliation(s)
- Hyowon Mun
- Molecular Medicine Laboratory, Department of Life systems, Sookmyung Women's University, Cheongpa-ro 47-gil 100, Yongsan-gu, Seoul, 04310, South Korea
| | - Jong Hoon Park
- Department of Life systems, Sookmyung Women's University, Cheongpa-ro 47-gil 100, Yongsan-gu, Seoul, 04310, South Korea.
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Ta MHT, Liuwantara D, Rangan GK. Effects of pyrrolidine dithiocarbamate on proliferation and nuclear factor-κB activity in autosomal dominant polycystic kidney disease cells. BMC Nephrol 2015; 16:212. [PMID: 26666710 PMCID: PMC4678764 DOI: 10.1186/s12882-015-0193-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Accepted: 11/24/2015] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Pyrrolidine dithiocarbamate (PDTC) reduces renal cyst growth in a rodent model of polycystic kidney disease (PKD) but the mechanism of action is not clear. Here, we investigated the hypothesis that PDTC reduces the proliferation of cystic epithelial cells in vitro in a nuclear factor (NF)-κB-dependent manner. METHODS Immortalized autosomal dominant PKD (ADPKD) cells that are heterozygous (WT9-7) and homozygous (WT-9-12) for a truncating Pkd1 mutation, and immortalized normal human tubular cells (HK-2), were exposed to NF-κB-inducing agents with or without PDTC. Cell proliferation and apoptosis were assessed by bromodeoxyuridine assay and Annexin V flow cytometry, respectively. NF-κB activity was assessed by luciferase reporter assay and western blotting for nuclear p65, p50, and RelB subunits and cytoplasmic phosphorylated-IκBα. RESULTS Serum-induced proliferation was similar in all cell lines over 72 h. PDTC demonstrated anti-proliferative effects that were delayed in ADPKD cells compared to HK-2. Basal NF-κB-dependent luciferase reporter activity was lower in ADPKD cells compared to normal cells. Classical NF-κB stimulants, lipopolysaccharide (LPS) and tumor necrosis factor (TNF)-α, increased NF-κB luciferase activity in HK-2, whereas in PKD cell lines, NF-κB activity was only induced by TNF-α. However, neither stimulant altered proliferation in any cell line. PDTC reduced TNF-α-stimulated NF-κB activity in HK-2 only. CONCLUSIONS PDTC reduced proliferation in ADPKD cells but did not consistently alter NF-κB activation, suggesting that other signalling pathways are likely to be involved in its ability to attenuate renal cyst growth in vivo.
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Affiliation(s)
- Michelle H T Ta
- Centre for Transplant and Renal Research, Level 5, The Westmead Institute for Medical Research, University of Sydney, 176 Hawkesbury Rd, Westmead, NSW, 2145, Australia.
| | - David Liuwantara
- Centre for Transplant and Renal Research, Level 5, The Westmead Institute for Medical Research, University of Sydney, 176 Hawkesbury Rd, Westmead, NSW, 2145, Australia.
| | - Gopala K Rangan
- Centre for Transplant and Renal Research, Level 5, The Westmead Institute for Medical Research, University of Sydney, 176 Hawkesbury Rd, Westmead, NSW, 2145, Australia.
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Development of renal cysts after crizotinib treatment in advanced ALK-positive non-small-cell lung cancer. J Thorac Oncol 2015; 9:1720-5. [PMID: 25436806 DOI: 10.1097/jto.0000000000000326] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
INTRODUCTION The development of complex renal cysts after crizotinib treatment for non-small-cell lung cancer (NSCLC) is a reported side effect. However, its occurrence and characteristics have not been reported. METHODS Medical records and computed tomography images of crizotinib-treated patients in three prospective clinical trials were reviewed. The size and Bosniak category of the renal cysts before and after crizotinib treatment were determined. Patients' clinical characteristics, tumor stage, treatment response, renal function, and outcomes were analyzed. RESULTS During December 2010 to March 2013, we enrolled 32 patients who received crizotinib. There were 23 patients who had renal cysts before crizotinib. The median follow-up time was 493 days. Seven patients (22%, six with baseline renal cyst and one without baseline renal cyst) had significant renal cyst change. Four (13% of all) had new complex renal cysts. The median time from crizotinib treatment to first recognization of significant renal cyst change was 77 days. After stopping crizotinib, complex renal cysts regressed significantly. Patients with significant renal cyst change received more previous anticancer therapy (median, 5 lines versus 3 lines, p = 0.04) and received crizotinib for longer duration (median, 956 days versus 248 days, p = 0.007) compared with those without significant renal cyst change. CONCLUSIONS Change of renal cysts after crizotinib treatment is not uncommon. Development of complex renal cysts reverses after stopping crizotinib.
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Chebib FT, Sussman CR, Wang X, Harris PC, Torres VE. Vasopressin and disruption of calcium signalling in polycystic kidney disease. Nat Rev Nephrol 2015; 11:451-64. [PMID: 25870007 PMCID: PMC4539141 DOI: 10.1038/nrneph.2015.39] [Citation(s) in RCA: 87] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic kidney disease and is responsible for 5-10% of cases of end-stage renal disease worldwide. ADPKD is characterized by the relentless development and growth of cysts, which cause progressive kidney enlargement associated with hypertension, pain, reduced quality of life and eventual kidney failure. Mutations in the PKD1 or PKD2 genes, which encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively, cause ADPKD. However, neither the functions of these proteins nor the molecular mechanisms of ADPKD pathogenesis are well understood. Here, we review the literature that examines how reduced levels of functional PC1 or PC2 at the primary cilia and/or the endoplasmic reticulum directly disrupts intracellular calcium signalling and indirectly disrupts calcium-regulated cAMP and purinergic signalling. We propose a hypothetical model in which dysregulated metabolism of cAMP and purinergic signalling increases the sensitivity of principal cells in collecting ducts and of tubular epithelial cells in the distal nephron to the constant tonic action of vasopressin. The resulting magnified response to vasopressin further enhances the disruption of calcium signalling that is initiated by mutations in PC1 or PC2, and activates downstream signalling pathways that cause impaired tubulogenesis, increased cell proliferation, increased fluid secretion and interstitial inflammation.
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Affiliation(s)
- Fouad T Chebib
- Division of Nephrology and Hypertension, 200 First Street S. W., Mayo Clinic College of Medicine, Rochester, MN 55901, USA
| | - Caroline R Sussman
- Division of Nephrology and Hypertension, 200 First Street S. W., Mayo Clinic College of Medicine, Rochester, MN 55901, USA
| | - Xiaofang Wang
- Division of Nephrology and Hypertension, 200 First Street S. W., Mayo Clinic College of Medicine, Rochester, MN 55901, USA
| | - Peter C Harris
- Division of Nephrology and Hypertension, 200 First Street S. W., Mayo Clinic College of Medicine, Rochester, MN 55901, USA
| | - Vicente E Torres
- Division of Nephrology and Hypertension, 200 First Street S. W., Mayo Clinic College of Medicine, Rochester, MN 55901, USA
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Wan C, Zhang Y, Jiang J, Jiang S, Nie X, Li A, Guo A, Wu Q. Critical Role of TAK1-Dependent Nuclear Factor-κB Signaling in 2,3,7,8-Tetrachlorodibenzo-p-dioxin-induced Astrocyte Activation and Subsequent Neuronal Death. Neurochem Res 2015; 40:1220-31. [PMID: 25998883 DOI: 10.1007/s11064-015-1585-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2014] [Revised: 02/02/2015] [Accepted: 04/20/2015] [Indexed: 12/21/2022]
Abstract
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been recently shown to elicit inflammatory response in a number of cell-types. However, whether TCDD could provoke inflammation in astrocytes, the most abundant glial cells in central nervous system (CNS), remains virtually unknown. In the present study, we showed that TCDD exposure could induce evident astrocyte activation both in vivo and in vitro. Further, we found that TGF-β-activated kinase 1 (TAK1), a critical regulator of NF-κB signaling, was rapidly phosphorylated in the process of TCDD-induced reactive astroglia. Exposure to TCDD led to rapid TAK1 and NF-κB p65 phosphorylation, as well as IKBα degradation. Moreover, blockage of TAK1 using siRNA oligos or TAK1 inhibitor 5Z-7-oxozeaenol significantly attenuated TCDD-induced astrocyte activation as well as the release of TNF-α. Finally, we showed that the conditioned medium of TCDD-treated astrocytes promoted the apoptosis of PC12 neuronal cells, which could be blocked with the pre-treatment of TAK1 inhibitor. Taken together, these findings suggested that TCDD could promote the inflammatory activation of astrocytes through modulating TAK1-NF-κB cascade, implicating that reactive astrocytes might contribute to TCDD-induced adverse effects on CNS system.
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Affiliation(s)
- Chunhua Wan
- Department of Nutrition and Food Hygieney, School of Public Health, Nantong University, Nantong, 226001, Jiangsu Province, People's Republic of China
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LaRiviere WB, Irazabal MV, Torres VE. Novel therapeutic approaches to autosomal dominant polycystic kidney disease. Transl Res 2015; 165:488-98. [PMID: 25438190 PMCID: PMC4363282 DOI: 10.1016/j.trsl.2014.11.003] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2014] [Revised: 10/17/2014] [Accepted: 11/06/2014] [Indexed: 01/14/2023]
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder characterized by the progressive growth of renal cysts that, over time, destroy the architecture of the renal parenchyma and typically lead to kidney failure by the sixth decade of life. ADPKD is common and represents a leading cause of renal failure worldwide. Currently, there are no Food and Drug Administration-approved treatments for the disease, and the existing standard of care is primarily supportive in nature. However, significant advances in the understanding of the molecular biology of the disease have inspired investigation into potential new therapies. Several drugs designed to slow or arrest the progression of ADPKD have shown promise in preclinical models and clinical trials, including vasopressin receptor antagonists and somatostatin analogs. This article examines the literature underlying the rationale for molecular therapies for ADPKD and reviews the existing clinical evidence for their indication for human patients with the disease.
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Affiliation(s)
- Wells B LaRiviere
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minn
| | - Maria V Irazabal
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minn
| | - Vicente E Torres
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minn.
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Ta MHT, Rao P, Korgaonkar M, Foster SF, Peduto A, Harris DCH, Rangan GK. Pyrrolidine dithiocarbamate reduces the progression of total kidney volume and cyst enlargement in experimental polycystic kidney disease. Physiol Rep 2014; 2:2/12/e12196. [PMID: 25501440 PMCID: PMC4332200 DOI: 10.14814/phy2.12196] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Heterocyclic dithiocarbamates have anti‐inflammatory and anti‐proliferative effects in rodent models of chronic kidney disease. In this study, we tested the hypothesis that pyrrolidine dithiocarbamate (PDTC) reduces the progression of polycystic kidney disease (PKD). Male Lewis polycystic kidney (LPK) rats (an ortholog of Nek8/NPHP9) received intraperitoneal injections of either saline vehicle or PDTC (40 mg/kg once or twice daily) from postnatal weeks 4 until 11. By serial magnetic resonance imaging at weeks 5 and 10, the relative within‐rat increase in total kidney volume and cyst volume were 1.3‐fold (P =0.01) and 1.4‐fold (P < 0.01) greater, respectively, in LPK + Vehicle compared to the LPK + PDTC(40 mg/kg twice daily) group. At week 11 in LPK rats, PDTC attenuated the increase in kidney weight to body weight ratio by 25% (P < 0.01) and proteinuria by 66% (P < 0.05 vs. LPK + Vehicle) but did not improve renal dysfunction. By quantitative whole‐slide image analysis, PDTC did not alter interstitial CD68+ cell accumulation, interstitial fibrosis, or renal cell proliferation in LPK rats at week 11. The phosphorylated form of the nuclear factor (NF)‐κB subunit, p105, was increased in cystic epithelial cells of LPK rats, but was not altered by PDTC. Moreover, PDTC did not significantly alter nuclear expression of the p50 subunit or NF‐κB (p65)‐DNA binding. Kidney enlargement in LPK rats was resistant to chronic treatment with a proteasome inhibitor, bortezomib. In conclusion, PDTC reduced renal cystic enlargement and proteinuria but lacked anti‐inflammatory effects in LPK rats. Lewis polycystic kidney rats were treated with pyrrolidine dithiocarbamate (PDTC) from weeks 4 to 11. Quantitative analysis of serial magnetic resonance images indicated that over time, the change in total kidney volume was 1.3‐fold higher in PDTC‐treated than in vehicle‐treated rats. PDTC treatment also decreased kidney weight to body weight ratio, renal cystic volume, and proteinuria.
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Affiliation(s)
- Michelle H T Ta
- Michael Stern Laboratory for Polycystic Kidney Disease, Centre for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia
| | - Padmashree Rao
- Michael Stern Laboratory for Polycystic Kidney Disease, Centre for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia
| | - Mayuresh Korgaonkar
- Brain Dynamics Centre, Westmead Millennium Institute, Westmead Hospital, University of Sydney, Sydney, New South Wales, Australia
| | - Sheryl F Foster
- Department of Radiology, Westmead Hospital and The University of Sydney, Sydney, New South Wales, Australia
| | - Anthony Peduto
- Department of Radiology, Westmead Hospital and The University of Sydney, Sydney, New South Wales, Australia
| | - David C H Harris
- Michael Stern Laboratory for Polycystic Kidney Disease, Centre for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia
| | - Gopala K Rangan
- Michael Stern Laboratory for Polycystic Kidney Disease, Centre for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia
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40
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Girard N, Audigier-Valette C, Cortot AB, Mennecier B, Debieuvre D, Planchard D, Zalcman G, Moro-Sibilot D, Cadranel J, Barlési F. ALK-rearranged non-small cell lung cancers: how best to optimize the safety of crizotinib in clinical practice? Expert Rev Anticancer Ther 2014; 15:225-33. [PMID: 25413260 DOI: 10.1586/14737140.2014.986103] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Crizotinib (XALKORI™, Pfizer) is a tyrosine kinase inhibitor targeting ALK, MET and ROS1, currently approved for the treatment of adults with ALK-rearranged non-small-cell lung cancer. Optimizing the management of frequent crizotinib-related adverse events is crucial to ensure its continuous administration and reproduce the response and survival rates reported in clinical trials. Here, we propose some practical measures, which are mostly derived from the recommendations given to the investigators of the PROFILE 1001, 1005, 1007 and 1014 trials and are based on experience and scientific findings regarding the management of these disorders. While visual disturbances or bradycardia are frequent but benign, the severity of the cardiac and hepatic adverse events requires special attention potential to QT interval prolongations and to the monitoring of electrolyte levels and liver function, taking into account potential drug-drug interactions.
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Affiliation(s)
- Nicolas Girard
- Department of Respiratory Medicine and Thoracic Oncology, Hôpital Louis Pradel, Hospices Civils de Lyon, Claude Bernard University Lyon 1, Lyon, France
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[ALK-rearranged non-small cell lung cancer: how to optimize treatment with crizotinib in routine practice?]. Bull Cancer 2014; 101:823-31. [PMID: 25299566 DOI: 10.1684/bdc.2014.1976] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Crizotinib (XALKORI(™), Pfizer) is a tyrosine kinase inhibitor of ALK, MET, and ROS1, which is currently approved for the second line treatment for ALK-rearranged lung cancer. This work from an expert group, based on the review of the data from the Profile studies, aims to provide practical elements in order to optimize the tolerability of crizotinib. Specific major or frequent side effects of crizotinib are discussed: visual disturbances, cardiac effects, elevated transaminases, and hypogonadism. In the routine practice, patients should be advised about visual disturbances, especially with regard to driving in low brightness. Digestive disorders related to crizotinib are exceptionally persistent or severe. Dietary measures and symptomatic treatments usually control these disorders. It is recommended to perform an electrocardiogram before introduction of crizotinib, to identify prolonged QT interval. Torsades de pointes may produce dizziness or syncope. Hypogonadism should be considered in case of fatigue, decreased libido, and even depression, taking into account that these symptoms may be related to cancer; testosterone serum level should be measured to identify patients that may be eligible to receive a supplementation. Monitoring of liver function tests, including transaminases and bilirubin, is necessary. To conclude, these practical elements are helpful to optimize treatment with crizotinib in patients with ALK-rearranged lung cancer; in the future, academic initiatives should be taken to study these aspects, based on the monitoring of large cohorts of patients treated with crizotinib.
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Paul BM, Vanden Heuvel GB. Kidney: polycystic kidney disease. WILEY INTERDISCIPLINARY REVIEWS-DEVELOPMENTAL BIOLOGY 2014; 3:465-87. [PMID: 25186187 DOI: 10.1002/wdev.152] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 08/31/2011] [Revised: 07/14/2014] [Accepted: 07/29/2014] [Indexed: 12/22/2022]
Abstract
Polycystic kidney disease (PKD) is a life-threatening genetic disorder characterized by the presence of fluid-filled cysts primarily in the kidneys. PKD can be inherited as autosomal recessive (ARPKD) or autosomal dominant (ADPKD) traits. Mutations in either the PKD1 or PKD2 genes, which encode polycystin 1 and polycystin 2, are the underlying cause of ADPKD. Progressive cyst formation and renal enlargement lead to renal insufficiency in these patients, which need to be managed by lifelong dialysis or renal transplantation. While characteristic features of PKD are abnormalities in epithelial cell proliferation, fluid secretion, extracellular matrix and differentiation, the molecular mechanisms underlying these events are not understood. Here we review the progress that has been made in defining the function of the polycystins, and how disruption of these functions may be involved in cystogenesis.
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Affiliation(s)
- Binu M Paul
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA
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Jerman S, Ward HH, Lee R, Lopes CAM, Fry AM, MacDougall M, Wandinger-Ness A. OFD1 and flotillins are integral components of a ciliary signaling protein complex organized by polycystins in renal epithelia and odontoblasts. PLoS One 2014; 9:e106330. [PMID: 25180832 PMCID: PMC4152239 DOI: 10.1371/journal.pone.0106330] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2014] [Accepted: 07/31/2014] [Indexed: 12/16/2022] Open
Abstract
Mutation of the X-linked oral-facial-digital syndrome type 1 (OFD1) gene is embryonic lethal in males and results in craniofacial malformations and adult onset polycystic kidney disease in females. While the OFD1 protein localizes to centriolar satellites, centrosomes and basal bodies, its cellular function and how it relates to cystic kidney disease is largely unknown. Here, we demonstrate that OFD1 is assembled into a protein complex that is localized to the primary cilium and contains the epidermal growth factor receptor (EGFR) and domain organizing flotillin proteins. This protein complex, which has similarity to a basolateral adhesion domain formed during cell polarization, also contains the polycystin proteins that when mutant cause autosomal dominant polycystic kidney disease (ADPKD). Importantly, in human ADPKD cells where mutant polycystin-1 fails to localize to cilia, there is a concomitant loss of localization of polycystin-2, OFD1, EGFR and flotillin-1 to cilia. Together, these data suggest that polycystins are necessary for assembly of a novel flotillin-containing ciliary signaling complex and provide a molecular rationale for the common renal pathologies caused by OFD1 and PKD mutations.
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Affiliation(s)
- Stephanie Jerman
- Department of Pathology MSC08-4640 and Cancer Research and Treatment Center, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States of America
| | - Heather H. Ward
- Department of Internal Medicine, Division of Nephrology MSC10-5550, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States of America
| | - Rebecca Lee
- Department of Pathology MSC08-4640 and Cancer Research and Treatment Center, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States of America
| | - Carla A. M. Lopes
- Department of Biochemistry, University of Leicester, Leicester, United Kingdom
| | - Andrew M. Fry
- Department of Biochemistry, University of Leicester, Leicester, United Kingdom
| | - Mary MacDougall
- Institute of Oral Health Research & Department of Oral and Maxillofacial Surgery, School of Dentistry, University of Alabama, Birmingham, Alabama, United States of America
| | - Angela Wandinger-Ness
- Department of Pathology MSC08-4640 and Cancer Research and Treatment Center, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States of America
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Harris PC, Torres VE. Genetic mechanisms and signaling pathways in autosomal dominant polycystic kidney disease. J Clin Invest 2014; 124:2315-24. [PMID: 24892705 DOI: 10.1172/jci72272] [Citation(s) in RCA: 243] [Impact Index Per Article: 22.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Recent advances in defining the genetic mechanisms of disease causation and modification in autosomal dominant polycystic kidney disease (ADPKD) have helped to explain some extreme disease manifestations and other phenotypic variability. Studies of the ADPKD proteins, polycystin-1 and -2, and the development and characterization of animal models that better mimic the human disease, have also helped us to understand pathogenesis and facilitated treatment evaluation. In addition, an improved understanding of aberrant downstream pathways in ADPKD, such as proliferation/secretion-related signaling, energy metabolism, and activated macrophages, in which cAMP and calcium changes may play a role, is leading to the identification of therapeutic targets. Finally, results from recent and ongoing preclinical and clinical trials are greatly improving the prospects for available, effective ADPKD treatments.
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Tran PV, Sharma M, Li X, Calvet JP. Developmental signaling: does it bridge the gap between cilia dysfunction and renal cystogenesis? ACTA ACUST UNITED AC 2014; 102:159-73. [PMID: 24861210 DOI: 10.1002/bdrc.21065] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2014] [Accepted: 04/14/2014] [Indexed: 01/05/2023]
Abstract
For more than a decade, evidence has accumulated linking dysfunction of primary cilia to renal cystogenesis, yet molecular mechanisms remain undefined. The pathogenesis of renal cysts is complex, involving multiple cellular aberrations and signaling pathways. Adding to this complexity, primary cilia exhibit multiple roles in a context-dependent manner. On renal epithelial cells, primary cilia act as mechanosensors and trigger extracellular Ca(2+) influx in response to laminar fluid flow. During mammalian development, primary cilia mediate the Hedgehog (Hh), Wnt, and Notch pathways, which control cell proliferation and differentiation, and tissue morphogenesis. Further, experimental evidence suggests the developmental state of the kidney strongly influences renal cystic disease. Thus, we review evidence for regulation of Ca(2+) and cAMP, key molecules in renal cystogenesis, at the primary cilium, the role of Hh, Wnt, and Notch signaling in renal cystic disease, and the interplay between these developmental pathways and Ca(2+) signaling. Indeed if these developmental pathways influence renal cystogenesis, these may represent novel therapeutic targets that can be integrated into a combination therapy for renal cystic disease.
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Affiliation(s)
- Pamela V Tran
- Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas; The Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas
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46
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Eccles MR, Stayner CA. Polycystic kidney disease - where gene dosage counts. F1000PRIME REPORTS 2014; 6:24. [PMID: 24765529 PMCID: PMC3974567 DOI: 10.12703/p6-24] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Gene dosage effects have emerged as playing a central role in the pathogenesis of polycystic kidney disease. Yet, how gene dosage can ultimately have an impact on the formation of kidney cysts remains unknown. In this commentary we review the evidence for the role of gene dosage effects versus the “2-hit” mutation model in polycystic kidney disease (PKD), and also discuss how gene networks may potentially make intertwined contributions to PKD.
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Osmoregulation, vasopressin, and cAMP signaling in autosomal dominant polycystic kidney disease. Curr Opin Nephrol Hypertens 2014; 22:459-70. [PMID: 23736843 DOI: 10.1097/mnh.0b013e3283621510] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent inherited nephropathy. This review will focus on the vasopressin and 3'-5'-cyclic adenosine monophosphate (cAMP) signaling pathways in ADPKD and will discuss how these insights offer new possibilities for the follow-up and treatment of the disease. RECENT FINDINGS Defective osmoregulation is an early manifestation of ADPKD and originates from both peripheral (renal effect of vasopressin) and central (release of vasopressin) components. Copeptin, which is released from the vasopressin precursor, may identify ADPKD patients at risk for rapid disease progression. Increased levels of cAMP in tubular cells, reflecting modifications in intracellular calcium homeostasis and abnormal stimulation of the vasopressin V2 receptor (V2R), play a central role in cystogenesis. Blocking the V2R lowers cAMP in cystic tissues, slows renal cystic progression and improves renal function in preclinical models. A phase III clinical trial investigating the effect of the V2R antagonist tolvaptan in ADPKD patients has shown that this treatment blunts kidney growth, reduces associated symptoms and slows kidney function decline when given over 3 years. SUMMARY These advances open perspectives for the understanding of cystogenesis in ADPKD, the mechanisms of osmoregulation, the role of polycystins in the brain, and the pleiotropic action of vasopressin.
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Torres VE, Harris PC. Strategies targeting cAMP signaling in the treatment of polycystic kidney disease. J Am Soc Nephrol 2014; 25:18-32. [PMID: 24335972 PMCID: PMC3871779 DOI: 10.1681/asn.2013040398] [Citation(s) in RCA: 185] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Polycystic kidney disease (PKD) is a leading cause of ESRD worldwide. In PKD, excessive cell proliferation and fluid secretion, pathogenic interactions of mutated epithelial cells with an abnormal extracellular matrix and alternatively activated interstitial macrophages, and the disruption of mechanisms controlling tubular diameter contribute to cyst formation. Studies with animal models suggest that several diverse pathophysiologic mechanisms, including dysregulation of intracellular calcium levels and cAMP signaling, mediate these cystogenic mechanisms. This article reviews the evidence implicating calcium and cAMP as central players in a network of signaling pathways underlying the pathogenesis of PKD and considers the therapeutic relevance of treatment strategies targeting cAMP signaling.
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Affiliation(s)
- Vicente E Torres
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
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Spirli C, Locatelli L, Morell CM, Fiorotto R, Morton SD, Cadamuro M, Fabris L, Strazzabosco M. Protein kinase A-dependent pSer(675) -β-catenin, a novel signaling defect in a mouse model of congenital hepatic fibrosis. Hepatology 2013; 58:1713-23. [PMID: 23744610 PMCID: PMC3800498 DOI: 10.1002/hep.26554] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2013] [Revised: 05/16/2013] [Accepted: 05/24/2013] [Indexed: 12/16/2022]
Abstract
UNLABELLED Genetically determined loss of fibrocystin function causes congenital hepatic fibrosis (CHF), Caroli disease (CD), and autosomal recessive polycystic kidney disease (ARPKD). Cystic dysplasia of the intrahepatic bile ducts and progressive portal fibrosis characterize liver pathology in CHF/CD. At a cellular level, several functional morphological and signaling changes have been reported including increased levels of 3'-5'-cyclic adenosine monophosphate (cAMP). In this study we addressed the relationships between increased cAMP and β-catenin. In cholangiocytes isolated and cultured from Pkhd1(del4/del4) mice, stimulation of cAMP/PKA signaling (forskolin 10 μM) stimulated Ser(675) -phosphorylation of β-catenin, its nuclear localization, and its transcriptional activity (western blot and TOP flash assay, respectively) along with a down-regulation of E-cadherin expression (immunocytochemistry and western blot); these changes were inhibited by the PKA blocker, PKI (1 μM). The Rho-GTPase, Rac-1, was also significantly activated by cAMP in Pkhd1(del4/del4) cholangiocytes. Rac-1 inhibition blocked cAMP-dependent nuclear translocation and transcriptional activity of pSer(675) -β-catenin. Cell migration (Boyden chambers) was significantly higher in cholangiocytes obtained from Pkhd1(del4/del4) and was inhibited by: (1) PKI, (2) silencing β-catenin (siRNA), and (3) the Rac-1 inhibitor NSC 23766. CONCLUSION These data show that in fibrocystin-defective cholangiocytes, cAMP/PKA signaling stimulates pSer(675) -phosphorylation of β-catenin and Rac-1 activity. In the presence of activated Rac-1, pSer(675) -β-catenin is translocated to the nucleus, becomes transcriptionally active, and is responsible for increased motility of Pkhd1(del4/del4) cholangiocytes. β-Catenin-dependent changes in cell motility may be central to the pathogenesis of the disease and represent a potential therapeutic target.
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Affiliation(s)
- Carlo Spirli
- Liver Center & Section of Digestive Diseases, Department of Internal Medicine, Yale University, New Haven, CT, USA
| | - Luigi Locatelli
- Department of InterdisciplinaryMedicine and Surgery, University of Milan-Bicocca, Milan, Italy
| | - Carola M. Morell
- Department of InterdisciplinaryMedicine and Surgery, University of Milan-Bicocca, Milan, Italy
| | - Romina Fiorotto
- Liver Center & Section of Digestive Diseases, Department of Internal Medicine, Yale University, New Haven, CT, USA
| | - Stuart D. Morton
- Department of Surgical, Oncological, and Gastroenterological Sciences, University of Padova, Padova, Italy
| | - Massimiliano Cadamuro
- Department of Surgical, Oncological, and Gastroenterological Sciences, University of Padova, Padova, Italy
- Department of InterdisciplinaryMedicine and Surgery, University of Milan-Bicocca, Milan, Italy
| | - Luca Fabris
- Department of Surgical, Oncological, and Gastroenterological Sciences, University of Padova, Padova, Italy
| | - Mario Strazzabosco
- Liver Center & Section of Digestive Diseases, Department of Internal Medicine, Yale University, New Haven, CT, USA
- Department of InterdisciplinaryMedicine and Surgery, University of Milan-Bicocca, Milan, Italy
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50
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Ta MHT, Harris DCH, Rangan GK. Role of interstitial inflammation in the pathogenesis of polycystic kidney disease. Nephrology (Carlton) 2013; 18:317-30. [DOI: 10.1111/nep.12045] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/20/2013] [Indexed: 12/12/2022]
Affiliation(s)
- Michelle HT Ta
- Centre for Transplant and Renal Research; Westmead Millennium Institute; The University of Sydney; Sydney; New South Wales; Australia
| | - David CH Harris
- Centre for Transplant and Renal Research; Westmead Millennium Institute; The University of Sydney; Sydney; New South Wales; Australia
| | - Gopala K Rangan
- Centre for Transplant and Renal Research; Westmead Millennium Institute; The University of Sydney; Sydney; New South Wales; Australia
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