|
1
|
Itabashi T, Hosoba K, Morita T, Kimura S, Yamaoka K, Hirosawa M, Kobayashi D, Kishi H, Kume K, Itoh H, Kawakami H, Hashimoto K, Yamamoto T, Miyamoto T. Cholesterol ensures ciliary polycystin-2 localization to prevent polycystic kidney disease. Life Sci Alliance 2025; 8:e202403063. [PMID: 39900437 PMCID: PMC11791027 DOI: 10.26508/lsa.202403063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 01/09/2025] [Accepted: 01/10/2025] [Indexed: 02/05/2025] Open
Abstract
The plasma membrane covering the primary cilium has a diverse accumulation of receptors and channels. To ensure the sensor function of the cilia, the ciliary membrane has higher cholesterol content than other cell membrane regions. A peroxisomal biogenesis disorder, Zellweger syndrome, characterized by polycystic kidney, is associated with a reduced level of ciliary cholesterol in cells. However, the etiological mechanism by which ciliary cholesterol lowering causes polycystic kidney disease remains unclear. Here, we demonstrated that lowering ciliary cholesterol by either pharmacological treatment or genetic depletion of peroxisomes impairs the localization of a ciliary ion channel polycystin-2. We also generated cultured renal medullary cells and mice carrying a missense variant in the cholesterol-binding site of polycystin-2 detected in the patient database of autosomal dominant polycystic kidney disease. This missense protein showed normal channel activity but decreased localization to the ciliary membrane. The homozygous mice exhibited embryonic lethality and the ciliopathy spectrum conditions of situs inversus and polycystic kidney. Our results suggest that cholesterol controls the ciliary localization of polycystin-2 to prevent polycystic kidney disease.
Collapse
Affiliation(s)
- Takeshi Itabashi
- Department of Molecular and Cellular Physiology, Graduate School of Medicine, Yamaguchi University, Yamaguchi, Japan
- Division of Advanced Genome Editing Therapy, Research Institute for Cell Design Medical Science, Yamaguchi University, Yamaguchi, Japan
| | - Kosuke Hosoba
- Program of Biomedical Science, Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, Japan
- Program of Mathematical and Life Science, Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, Japan
| | - Tomoka Morita
- Department of Molecular and Cellular Physiology, Graduate School of Medicine, Yamaguchi University, Yamaguchi, Japan
- Division of Advanced Genome Editing Therapy, Research Institute for Cell Design Medical Science, Yamaguchi University, Yamaguchi, Japan
| | - Sotai Kimura
- Department of Molecular Pathology, Graduate School of Medicine, Yamaguchi University, Yamaguchi, Japan
- Department of Anatomic Pathology, Hirosaki University Hospital, Aomori, Japan
| | - Kenji Yamaoka
- Department of Neurophysiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Moe Hirosawa
- Department of Molecular and Cellular Physiology, Graduate School of Medicine, Yamaguchi University, Yamaguchi, Japan
- Division of Advanced Genome Editing Therapy, Research Institute for Cell Design Medical Science, Yamaguchi University, Yamaguchi, Japan
| | - Daigo Kobayashi
- Department of Molecular and Cellular Physiology, Graduate School of Medicine, Yamaguchi University, Yamaguchi, Japan
| | - Hiroko Kishi
- Department of Molecular and Cellular Physiology, Graduate School of Medicine, Yamaguchi University, Yamaguchi, Japan
- Department of Environmental Physiology, Faculty of Medicine, Shimane University, Shimane, Japan
| | - Kodai Kume
- Department of Molecular Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | - Hiroshi Itoh
- Department of Molecular Pathology, Graduate School of Medicine, Yamaguchi University, Yamaguchi, Japan
| | - Hideshi Kawakami
- Department of Molecular Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | - Kouichi Hashimoto
- Department of Neurophysiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Takashi Yamamoto
- Program of Biomedical Science, Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, Japan
- Program of Mathematical and Life Science, Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, Japan
| | - Tatsuo Miyamoto
- Department of Molecular and Cellular Physiology, Graduate School of Medicine, Yamaguchi University, Yamaguchi, Japan
- Division of Advanced Genome Editing Therapy, Research Institute for Cell Design Medical Science, Yamaguchi University, Yamaguchi, Japan
| |
Collapse
|
|
2
|
Zhang Y, Zhang R, Shi X, Liu X, Li C, Zhang Y, Wang Z, Qiao D, Pan F, Zhang B, Xu N, Dong B, Shao L. Minigene-based splice assays provide new insights on intronic variants of the PKHD1 gene. Hum Genomics 2024; 18:122. [PMID: 39521997 PMCID: PMC11550526 DOI: 10.1186/s40246-024-00675-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Accepted: 09/18/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Autosomal Recessive Polycystic Kidney Disease (ARPKD) is a rare hereditary disorder caused by variants in PKHD1. Currently, aberrant splicing has been reported to play important roles in genetic disease. Our goal is to analyze intronic variants in PKHD1 at the mRNA level. RESULTS The 12 candidate variants were introduced into the corresponding minigene and functionally assayed in HEK 293T and Hela cells. We identified 11 variants that induce splicing alterations, resulting in various consequences such as skipping of exons, intron retention and protein truncation. CONCLUSIONS This underlined the importance of mRNA-level assessment for genetic diagnostics in related genetic disorders.
Collapse
Affiliation(s)
- Yiyin Zhang
- Department of Nephrology, The Affiliated Municipal Hospital of Qingdao University, No.5 Donghai Middle Road, Qingdao, 266071, China
| | - Ran Zhang
- Department of Nephrology, The Affiliated Municipal Hospital of Qingdao University, No.5 Donghai Middle Road, Qingdao, 266071, China
| | - Xiaomeng Shi
- Department of Nephrology, The Affiliated Municipal Hospital of Qingdao University, No.5 Donghai Middle Road, Qingdao, 266071, China
| | - Xuyan Liu
- Department of Nephrology, The Affiliated Municipal Hospital of Qingdao University, No.5 Donghai Middle Road, Qingdao, 266071, China
| | - Changying Li
- Department of Nephrology, The Affiliated Municipal Hospital of Qingdao University, No.5 Donghai Middle Road, Qingdao, 266071, China
| | - Yan Zhang
- School of Clinical Medicine, Shandong Second Medical University, Weifang, 261000, China
| | - Zhi Wang
- School of Clinical Medicine, Shandong Second Medical University, Weifang, 261000, China
| | - Dan Qiao
- Department of Nephrology, Dalian Medical University, Dalian, 116000, China
| | - Fengjiao Pan
- Department of Nephrology, The Affiliated Municipal Hospital of Qingdao University, No.5 Donghai Middle Road, Qingdao, 266071, China
| | - Bingying Zhang
- School of Clinical Medicine, Shandong Second Medical University, Weifang, 261000, China
| | - Ning Xu
- Department of Nephrology, The Affiliated Municipal Hospital of Qingdao University, No.5 Donghai Middle Road, Qingdao, 266071, China
| | - Bingzi Dong
- Department of Endocrinology, The Affiliated Hospital of Qingdao University, No.16 Jangsu Road, Qingdao, 266003, China.
| | - Leping Shao
- Department of Nephrology, The First Affiliated Hospital of Xiamen University, Xiamen, China.
| |
Collapse
|
|
3
|
Langner E, Puapatanakul P, Pudlowski R, Alsabbagh DY, Miner JH, Horani A, Dutcher SK, Brody SL, Wang JT, Suleiman HY, Mahjoub MR. Ultrastructure expansion microscopy (U-ExM) of mouse and human kidneys for analysis of subcellular structures. Cytoskeleton (Hoboken) 2024; 81:618-638. [PMID: 38715433 PMCID: PMC11540979 DOI: 10.1002/cm.21870] [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: 02/16/2024] [Revised: 04/11/2024] [Accepted: 04/22/2024] [Indexed: 05/21/2024]
Abstract
Ultrastructure expansion microscopy (U-ExM) involves the physical magnification of specimens embedded in hydrogels, which allows for super-resolution imaging of subcellular structures using a conventional diffraction-limited microscope. Methods for expansion microscopy exist for several organisms, organs, and cell types, and used to analyze cellular organelles and substructures in nanoscale resolution. Here, we describe a simple step-by-step U-ExM protocol for the expansion, immunostaining, imaging, and analysis of cytoskeletal and organellar structures in kidney tissue. We detail the critical modified steps to optimize isotropic kidney tissue expansion, and preservation of the renal cell structures of interest. We demonstrate the utility of the approach using several markers of renal cell types, centrioles, cilia, the extracellular matrix, and other cytoskeletal elements. Finally, we show that the approach works well on mouse and human kidney samples that were preserved using different fixation and embedding conditions. Overall, this protocol provides a simple and cost-effective approach to analyze both preclinical and clinical renal samples in high detail, using conventional lab supplies and standard widefield or confocal microscopy.
Collapse
Affiliation(s)
- Ewa Langner
- Department of Medicine, Washington University, St. Louis, Missouri, USA
| | - Pongpratch Puapatanakul
- Department of Medicine, Washington University, St. Louis, Missouri, USA
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Rachel Pudlowski
- Department of Biology, Washington University, St. Louis, Missouri, USA
| | | | - Jeffrey H Miner
- Department of Medicine, Washington University, St. Louis, Missouri, USA
| | - Amjad Horani
- Department of Pediatrics, Washington University, St. Louis, Missouri, USA
| | - Susan K Dutcher
- Department of Genetics, Washington University, St. Louis, Missouri, USA
| | - Steven L Brody
- Department of Medicine, Washington University, St. Louis, Missouri, USA
| | - Jennifer T Wang
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Hani Y Suleiman
- Department of Medicine, Washington University, St. Louis, Missouri, USA
| | - Moe R Mahjoub
- Department of Medicine, Washington University, St. Louis, Missouri, USA
- Department of Cell Biology and Physiology, Washington University, St. Louis, Missouri, USA
| |
Collapse
|
|
4
|
Rai V, Singh M, Holthoff JH. New Mutation Associated with Polycystic Kidney Disease Type I: A Case Report. Genes (Basel) 2024; 15:1262. [PMID: 39457385 PMCID: PMC11507877 DOI: 10.3390/genes15101262] [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: 08/26/2024] [Revised: 09/17/2024] [Accepted: 09/25/2024] [Indexed: 10/28/2024] Open
Abstract
INTRODUCTION Autosomal dominant polycystic kidney disease (ADPKD) is one of the most prevalent heritable disorders, characterized by the progressive development of kidney cysts leading to renal failure. It is primarily caused by mutations in the PKD1 and PKD2 genes, which account for approximately 85% and 15% of cases, respectively. This case report describes a previously unreported mutation in the PKD1 gene, identified in a family involving an aunt and her niece with ADPKD. CASE PRESENTATION The index case, a 56-year-old female with chronic kidney disease stage 3b secondary to ADPKD and hypertension, exhibited a strong family history of polycystic kidney disease (PKD). Initial genetic evaluations did not identify any recognized pathogenic mutations, leading to a more detailed investigation which revealed a novel mutation in the PKD1 gene. This mutation was also found in her niece, who presented with early-onset disease. CONCLUSIONS The identification of a heterozygous six-nucleotide deletion, c.2084_2089del, resulting in the in-frame deletion of two amino acids, p.Pro695_Ala696del, in the PKD1 gene, has been linked with ADPKD in these patients. This report emphasizes the need for continuous updates to genetic data for a deeper understanding of the diagnosis and prognosis of ADPKD that could potentially aid in targeted therapy.
Collapse
Affiliation(s)
- Vanya Rai
- Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA;
| | - Manisha Singh
- Department of Nephrology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA;
| | - Joseph H. Holthoff
- Department of Nephrology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA;
| |
Collapse
|
|
5
|
Yuan J, Shao Z, Lv M, Li K, Wei Z. Identification of deleterious variants in nine polycystic kidney disease affected families. Gene 2024; 919:148505. [PMID: 38670396 DOI: 10.1016/j.gene.2024.148505] [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: 12/08/2023] [Revised: 04/01/2024] [Accepted: 04/23/2024] [Indexed: 04/28/2024]
Abstract
Polycystic kidney disease (PKD) is common genetic renal disorder. In present study, we performed WES to identify pathogenic variant in nine families including 26 patients with PKD and 19 unaffected members. The eight pathogenic variants were identified in known PKD associated genes including PKD1 (n = 6), PKD2 (n = 1), and OFD1 (n = 1) in eight families. There is one missense, one stopgain, two non-frameshifts, two canonical splicing variants, three frameshift variants and one potential non-canonical splicing variant (NCSV) in 8 families. The six variants were novel variants and not reported in ClinVar database. In addition, the compound heterozygous variants in PKHD1 were identified including one frameshift variants (PKHD1: NM_138694.4, c.9841del, p.S3281Lfs*4) and one non-canonical splicing variant (PKHD1: NM_138694.4, c.6332 + 40A > G) which were defined as deleterious variant by four splicing prediction tools (CADD-splice, SpliceAI, Spliceogen, Squirl). We used the minigene method to validate whether the prioritized potential NSCVs disrupt the typical mRNA splicing process and found abnormally larger PCR production of minigene carrying potential NCSV comparing to wild-type minigene. Sanger sequencing confirmed the 39-bp insertion of intron 38 between exon 38 and exon 39, which results in non-frameshift and 13 amino acid insertions. In conclusion, our study expands the variant spectrum and highlight the important role of non-canonical splicing variant in PKD.
Collapse
Affiliation(s)
- Jing Yuan
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No 81 Meishan Road, Hefei 230032, Anhui, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, No 81 Meishan Road, Hefei 230032, Anhui, China
| | - Zhongmei Shao
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No 81 Meishan Road, Hefei 230032, Anhui, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, No 81 Meishan Road, Hefei 230032, Anhui, China
| | - Mingrong Lv
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No 81 Meishan Road, Hefei 230032, Anhui, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, No 81 Meishan Road, Hefei 230032, Anhui, China
| | - Kuokuo Li
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No 81 Meishan Road, Hefei 230032, Anhui, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, No 81 Meishan Road, Hefei 230032, Anhui, China.
| | - Zhaolian Wei
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No 81 Meishan Road, Hefei 230032, Anhui, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, No 81 Meishan Road, Hefei 230032, Anhui, China.
| |
Collapse
|
|
6
|
Rothem Y, Askenasy E, Siman-Tov M, Davidov Y, Hoffman T, Mor E, Hod T. Elevated hemoglobin levels in renal transplant recipients with polycystic kidney disease versus other etiologies: exploring mechanisms and implications for outcomes. J Nephrol 2024; 37:1523-1537. [PMID: 38427307 PMCID: PMC11473538 DOI: 10.1007/s40620-023-01868-6] [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: 10/13/2023] [Accepted: 12/14/2023] [Indexed: 03/02/2024]
Abstract
BACKGROUND Autosomal dominant polycystic kidney disease (ADPKD)-related end-stage kidney disease (ESKD) often necessitates transplantation. However, the impact of ADPKD on post-transplant outcomes, specifically hemoglobin levels, remains unknown. METHODS We retrospectively analyzed 513 Kidney Transplant Recipients (KTRs), of whom 81 had ESKD due to ADPKD (20 with pre-transplant native nephrectomy and 61 without). Hemoglobin levels were evaluated at multiple time intervals post-transplant. RESULTS Kidney transplant recipients with ADPKD vs. KTRs with ESKD due to other causes exhibited significantly higher hemoglobin levels in repeated measurement analysis. Multivariable analyses confirmed ADPKD as an independent predictor for elevated hemoglobin levels. In a multivariable logistic regression analysis, the odds for maximum hemoglobin > 15 mg/dL at 3-12 months post-transplant were more than twice as high in ADPKD patients vs. all the other KTRs (Odds Ratio [OR] 2.31, 95% Confidence Interval [CI] 1.3-4.13, p < 0.001). Pre-transplant native nephrectomy revealed a trend toward lower hemoglobin levels. Elevated hemoglobin levels were linked to improved estimated glomerular filtration rate (eGFR) at one year post-transplant. Patient survival was enhanced among KTRs with ADPKD compared to other ESKD causes. CONCLUSIONS Kidney transplant recipients with ADPKD exhibited elevated hemoglobin levels post-transplant, possibly due to prolonged native kidney erythropoietin production. These elevated hemoglobin levels were linked to improved outcomes, including allograft function and patient survival. Future research should further investigate the underlying mechanisms driving favorable ADPKD KTR outcomes.
Collapse
Affiliation(s)
- Yael Rothem
- Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel
| | - Enosh Askenasy
- Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel
- Renal Transplant Center, Sheba Medical Center, Tel Hashomer, Israel
| | - Maya Siman-Tov
- Department of Emergency and Disaster Management, School of Public Health, Tel-Aviv University, Tel Aviv, Israel
| | - Yana Davidov
- Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel
- Liver Disease Center, Sheba Medical Center, Tel Hashomer, Israel
| | - Tomer Hoffman
- Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel
- Infectious Diseases Unit, Sheba Medical Center, Tel Hashomer, Israel
| | - Eytan Mor
- Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel
- Renal Transplant Center, Sheba Medical Center, Tel Hashomer, Israel
| | - Tammy Hod
- Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel.
- Renal Transplant Center, Sheba Medical Center, Tel Hashomer, Israel.
| |
Collapse
|
|
7
|
Huang Y, Osouli A, Pham J, Mancino V, O'Grady C, Khan T, Chaudhuri B, Pastor-Soler NM, Hallows KR, Chung EJ. Investigation of Basolateral Targeting Micelles for Drug Delivery Applications in Polycystic Kidney Disease. Biomacromolecules 2024; 25:2749-2761. [PMID: 38652072 DOI: 10.1021/acs.biomac.3c01397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/25/2024]
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is a complex disorder characterized by uncontrolled renal cyst growth, leading to kidney function decline. The multifaceted nature of ADPKD suggests that single-pathway interventions using individual small molecule drugs may not be optimally effective. As such, a strategy encompassing combination therapy that addresses multiple ADPKD-associated signaling pathways could offer synergistic therapeutic results. However, severe off-targeting side effects of small molecule drugs pose a major hurdle to their clinical transition. To address this, we identified four drug candidates from ADPKD clinical trials, bardoxolone methyl (Bar), octreotide (Oct), salsalate (Sal), and pravastatin (Pra), and incorporated them into peptide amphiphile micelles containing the RGD peptide (GRGDSP), which binds to the basolateral surface of renal tubules via integrin receptors on the extracellular matrix. We hypothesized that encapsulating drug combinations into RGD micelles would enable targeting to the basolateral side of renal tubules, which is the site of disease, via renal secretion, leading to superior therapeutic benefits compared to free drugs. To test this, we first evaluated the synergistic effect of drug combinations using the 20% inhibitory concentration for each drug (IC20) on renal proximal tubule cells derived from Pkd1flox/-:TSLargeT mice. Next, we synthesized and characterized the RGD micelles encapsulated with drug combinations and measured their in vitro therapeutic effects via a 3D PKD growth model. Upon both IV and IP injections in vivo, RGD micelles showed a significantly higher accumulation in the kidneys compared to NT micelles, and the renal access of RGD micelles was significantly reduced after the inhibition of renal secretion. Specifically, both Bar+Oct and Bar+Sal in the RGD micelle treatment showed enhanced therapeutic efficacy in ADPKD mice (Pkd1fl/fl;Pax8-rtTA;Tet-O-Cre) with a significantly lower KW/BW ratio and cyst index as compared to PBS and free drug-treated controls, while other combinations did not show a significant difference. Hence, we demonstrate that renal targeting through basolateral targeting micelles enhances the therapeutic potential of combination therapy in genetic kidney disease.
Collapse
Affiliation(s)
- Yi Huang
- Department of Biomedical Engineering, University of Southern California, Los Angeles, California 90089, United States
| | - Ali Osouli
- Department of Biomedical Engineering, University of Southern California, Los Angeles, California 90089, United States
| | - Jessica Pham
- Department of Medicine, Division of Nephrology and Hypertension, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, United States
- USC/UKRO Kidney Research Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, United States
| | - Valeria Mancino
- Department of Medicine, Division of Nephrology and Hypertension, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, United States
- USC/UKRO Kidney Research Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, United States
| | - Colette O'Grady
- Department of Biomedical Engineering, University of Southern California, Los Angeles, California 90089, United States
| | - Taranatee Khan
- Department of Biomedical Engineering, University of Southern California, Los Angeles, California 90089, United States
| | - Baishali Chaudhuri
- Department of Biomedical Engineering, University of Southern California, Los Angeles, California 90089, United States
| | - Nuria M Pastor-Soler
- Department of Medicine, Division of Nephrology and Hypertension, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, United States
- USC/UKRO Kidney Research Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, United States
| | - Kenneth R Hallows
- Department of Medicine, Division of Nephrology and Hypertension, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, United States
- USC/UKRO Kidney Research Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, United States
| | - Eun Ji Chung
- Department of Biomedical Engineering, University of Southern California, Los Angeles, California 90089, United States
- Department of Medicine, Division of Nephrology and Hypertension, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, United States
- Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, California 90089, United States
- Department of Surgery, Division of Vascular Surgery and Endovascular Therapy, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, United States
- Department of Stem Cell Biology and Regenerative Medicine, University of Southern California, Los Angeles, California 90089, United States
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California 90033, United States
- Bridge Institute, University of Southern California, Los Angeles, California 90089, United States
| |
Collapse
|
|
8
|
Simmons KE, Ullman LS, Dahl NK. Kidney Stones Account for Increased Imaging Studies in Autosomal Dominant Polycystic Kidney Disease. KIDNEY360 2024; 5:707-714. [PMID: 38526140 PMCID: PMC11146651 DOI: 10.34067/kid.0000000000000424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 03/19/2024] [Indexed: 03/26/2024]
Abstract
Key Points Kidney stones are common in patients with autosomal dominant polycystic kidney disease compared with matched controls with CKD. The increase in imaging seen in patients with autosomal dominant polycystic kidney disease correlates with the kidney stone burden in these patients. Background Patients with autosomal dominant polycystic kidney disease (ADPKD) may have more imaging studies than patients with other forms of CKD. We characterized the imaging burden of patients with ADPKD relative to a CKD population to determine which factors lead to increased imaging in patients with ADPKD. Methods We retrospectively reviewed patients seen at Yale Nephrology between January 2012 and January 2021. We collected demographic, clinical, and imaging data through automated query and manual chart review. Eight hundred seven patients with ADPKD were matched to 4035 CKD controls on the basis of criteria of sex, race, ethnicity, CKD stage, hypertension, and diabetes, but not age. The number of abdominal imaging studies were compared between ADPKD and CKD groups, and the effect of kidney stone diagnosis was further evaluated. Chi-square and t tests were used to evaluate demographic variables, and Kruskal Wallis and negative binomial regression models were used to evaluate differences between abdominal imaging studies. Results Patients with ADPKD had a greater number of total abdominal imaging studies (P < 0.0001), ultrasounds (P < 0.0001), and magnetic resonance imagings (P = 0.02) compared with controls. In patients with preserved renal function (eGFR >60 ml/min per m2), these differences persisted. Kidney stones were significantly more common among patients with ADPKD (P < 0.0001). In multivariable assessment of imaging study counts using a negative binomial model controlling for kidney stones, ADPKD was no longer a significant predictor. In patients with ADPKD, pyelonephritis; cyst complications; lower eGFR; diabetes; coronary artery disease; kidney stones; lower body mass index; and being male, Black, and younger increased the likelihood of having more imaging studies. Conclusions The higher prevalence of abdominal imaging studies in patients with ADPKD correlated with the increased incidence of kidney stones observed in this population.
Collapse
Affiliation(s)
| | | | - Neera K. Dahl
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
| |
Collapse
|
|
9
|
Zhang J, Wang Y, Zhao Y, Liu F. A new atypical splice mutation in PKD2 leading to autosomal dominant polycystic kidney disease in a Chinese family. Singapore Med J 2024; 65:229-234. [PMID: 34749493 PMCID: PMC11132625 DOI: 10.11622/smedj.2021162] [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: 01/28/2018] [Accepted: 07/25/2021] [Indexed: 02/05/2023]
Abstract
INTRODUCTION Autosomal dominant polycystic kidney disease (ADPKD) is a very common hereditary renal disorder. Mutations in PKD1 and PKD2 , identified as disease-causing genes, account for 85% and 15% of the ADPKD cases, respectively. METHODS In this study, the mutation analysis of polycystic kidney disease (PKD) genes was performed in a Chinese family with suspected ADPKD using targeted clinical exome sequencing (CES). The candidate pathogenic variants were further tested by using Sanger sequencing and validated for co-segregation. In addition, reverse transcription-polymerase chain reaction (RT-PCR) was performed to test for abnormal splicing and assess its potential pathogenicity. RESULTS A novel atypical splicing mutation that belongs to unclassified variants (UCVs), IVS6+5G>C, was identified in three family members by CES and was shown to co-segregate only with the affected individuals. The RT-PCR revealed the abnormal splicing of exon 6, which thus caused truncating mutation. These findings suggested that the atypical splice site alteration, IVS6+5G>C, in the PKD2 gene was the potential pathogenic mutation leading to ADPKD in this Chinese family. CONCLUSION The data available in this study provided strong evidence that IVS6+5G>C is the potential pathogenic mutation for ADPKD. In addition, our findings emphasised the significance of functional analysis of UCVs and genotype-phenotype correlation in ADPKD.
Collapse
Affiliation(s)
- Junlin Zhang
- Division of Nephrology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Yiting Wang
- Division of Nephrology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Yingwang Zhao
- Joy Orient Translational Medicine Research Center Co Ltd, Beijing, China
| | - Fang Liu
- Division of Nephrology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| |
Collapse
|
|
10
|
Wei T, Zhang B, Tang W, Li X, Shuai Z, Tang T, Zhang Y, Deng L, Liu Q. A de novo PKD1 mutation in a Chinese family with autosomal dominant polycystic kidney disease. Medicine (Baltimore) 2024; 103:e27853. [PMID: 38552045 PMCID: PMC10977567 DOI: 10.1097/md.0000000000027853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Accepted: 11/02/2021] [Indexed: 04/02/2024] Open
Abstract
BACKGROUND PKD1, which has a relatively high mutation rate, is highly polymorphic, and the role of PKD1 is incompletely defined. In the current study, in order to determine the molecular etiology of a family with autosomal dominant polycystic kidney disease, the pathogenicity of an frameshift mutation in the PKD1 gene, c.9484delC, was evaluated. METHODS The family clinical data were collected. Whole exome sequencing analysis determined the level of this mutation in the proband's PKD1, and Sanger sequencing and bioinformatics analysis were performed. SIFT, Polyphen2, and MutationTaster were used to evaluate the conservation of the gene and pathogenicity of the identified mutations. SWISS-MODEL was used to predict and map the protein structure of PKD1 and mutant neonate proteins. RESULTS A novel c.9484delC (p.Arg3162Alafs*154) mutation of the PKD1 gene was identified by whole exome sequencing in the proband, which was confirmed by Sanger sequencing in his sister (II7). The same mutation was not detected in the healthy pedigree members. Random screening of 100 normal and end-stage renal disease patients did not identify the c.9484delC mutation. Bioinformatics analysis suggested that the mutation caused the 3162 nd amino acid substitution of arginine by alanine and a shift in the termination codon. As a result, the protein sequence was shortened from 4302 amino acids to 3314 amino acids, the protein structure was greatly changed, and the PLAT/LH2 domain was destroyed. Clustal analysis indicated that the altered amino acids were highly conserved in mammals. CONCLUSION A novel mutation in the PKD1 gene has been identified in an affected Chinese family. The mutation is probably responsible for a range of clinical manifestations for which reliable prenatal diagnosis and genetic counseling may be provided.
Collapse
Affiliation(s)
- Ting Wei
- Department of Medical Laboratory, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, China
- Department of Medical Laboratory, North Sichuan Medical College, Nanchong, China
| | - Bing Zhang
- Department of Medical Laboratory, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, China
| | - Wei Tang
- Department of Medical Laboratory, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, China
| | - Xin Li
- Department of Medical Laboratory, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, China
| | - Zhuang Shuai
- Department of Cardiology Medicine, the Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Tao Tang
- Department of Medical Laboratory, North Sichuan Medical College, Nanchong, China
| | - Yueyang Zhang
- Department of Medical Laboratory, North Sichuan Medical College, Nanchong, China
| | - Lin Deng
- Department of Medical Laboratory, North Sichuan Medical College, Nanchong, China
| | - Qingsong Liu
- Department of Prenatal Diagnosis, Chengdu Women’s and Children’s Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| |
Collapse
|
|
11
|
Pasquier N, Jaulin F, Peglion F. Inverted apicobasal polarity in health and disease. J Cell Sci 2024; 137:jcs261659. [PMID: 38465512 PMCID: PMC10984280 DOI: 10.1242/jcs.261659] [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] [Indexed: 03/12/2024] Open
Abstract
Apicobasal epithelial polarity controls the functional properties of most organs. Thus, there has been extensive research on the molecular intricacies governing the establishment and maintenance of cell polarity. Whereas loss of apicobasal polarity is a well-documented phenomenon associated with multiple diseases, less is known regarding another type of apicobasal polarity alteration - the inversion of polarity. In this Review, we provide a unifying definition of inverted polarity and discuss multiple scenarios in mammalian systems and human health and disease in which apical and basolateral membrane domains are interchanged. This includes mammalian embryo implantation, monogenic diseases and dissemination of cancer cell clusters. For each example, the functional consequences of polarity inversion are assessed, revealing shared outcomes, including modifications in immune surveillance, altered drug sensitivity and changes in adhesions to neighboring cells. Finally, we highlight the molecular alterations associated with inverted apicobasal polarity and provide a molecular framework to connect these changes with the core cell polarity machinery and to explain roles of polarity inversion in health and disease. Based on the current state of the field, failure to respond to extracellular matrix (ECM) cues, increased cellular contractility and membrane trafficking defects are likely to account for most cases of inverted apicobasal polarity.
Collapse
Affiliation(s)
- Nicolas Pasquier
- Collective Invasion Team, Inserm U-1279, Gustave Roussy, Villejuif F-94805, France
- Cell Adhesion and Cancer lab, University of Turku, FI-20520 Turku, Finland
| | - Fanny Jaulin
- Collective Invasion Team, Inserm U-1279, Gustave Roussy, Villejuif F-94805, France
| | - Florent Peglion
- Collective Invasion Team, Inserm U-1279, Gustave Roussy, Villejuif F-94805, France
| |
Collapse
|
|
12
|
Langner E, Puapatanakul P, Pudlowski R, Alsabbagh DY, Miner JH, Horani A, Dutcher SK, Brody SL, Wang JT, Suleiman HY, Mahjoub MR. Ultrastructure expansion microscopy (U-ExM) of mouse and human kidneys for analysis of subcellular structures. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.16.580708. [PMID: 38405695 PMCID: PMC10889020 DOI: 10.1101/2024.02.16.580708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/27/2024]
Abstract
Ultrastructure expansion microscopy (U-ExM) involves the physical magnification of specimens embedded in hydrogels, which allows for super-resolution imaging of subcellular structures using a conventional diffraction-limited microscope. Methods for expansion microscopy exist for several organisms, organs, and cell types, and used to analyze cellular organelles and substructures in nanoscale resolution. Here, we describe a simple step-by-step U-ExM protocol for the expansion, immunostaining, imaging, and analysis of cytoskeletal and organellar structures in kidney tissue. We detail the critical modified steps to optimize isotropic kidney tissue expansion, and preservation of the renal cell structures of interest. We demonstrate the utility of the approach using several markers of renal cell types, centrioles, cilia, the extracellular matrix, and other cytoskeletal elements. Finally, we show that the approach works well on mouse and human kidney samples that were preserved using different fixation and storage conditions. Overall, this protocol provides a simple and cost-effective approach to analyze both pre-clinical and clinical renal samples in high detail, using conventional lab supplies and standard widefield or confocal microscopy.
Collapse
|
|
13
|
Girme A, Gupta V. A Case Report of the Coexistence of Gastric Cancer With Polycystic Kidney and Liver Disease: Unveiling the Complexity. Cureus 2024; 16:e53574. [PMID: 38445116 PMCID: PMC10914406 DOI: 10.7759/cureus.53574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/04/2024] [Indexed: 03/07/2024] Open
Abstract
Polycystic kidney disease (PKD) is a genetic disorder that comprises multiple cystic lesions in the kidneys. The association of PKD with gastric cancer has been studied. We present a rare presentation of stomach cancer with polycystic liver and kidney disease. A male patient in his 40s presented with epigastric pain, nausea, retrosternal burning, and occasional episodes of vomiting. Esophagogastroduodenoscopy revealed ulceroproliferative growth in the prepyloric region. Biopsies revealed moderately differentiated adenocarcinoma which was confirmed by contrast-enhanced computed tomography of the abdomen and pelvis. This showed a chance finding of polycystic kidney and liver disease. After confirmation with a positron emission tomography scan, the patient was diagnosed with gastric carcinoma (cT3N1M0, Stage IIB) with polycystic kidney and liver disease. We provide a case of early-stage stomach cancer in a patient with PKD. More extensive research is needed for a better understanding of this association between polycystic kidney and liver disease and gastric cancer development, to achieve earlier diagnosis.
Collapse
Affiliation(s)
- Amit Girme
- General Surgery, Dr. D. Y. Patil Medical College, Hospital & Research Centre, Pune, IND
| | - Vernika Gupta
- General Surgery, Dr. D. Y. Patil Medical College, Hospital & Research Centre, Pune, IND
| |
Collapse
|
|
14
|
Yamahara K, Yasuda-Yamahara M, Kuwagata S, Chin-Kanasaki M, Kume S. Ketone Body Metabolism in Diabetic Kidney Disease. KIDNEY360 2024; 5:320-326. [PMID: 38227425 PMCID: PMC10914200 DOI: 10.34067/kid.0000000000000359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Accepted: 01/10/2024] [Indexed: 01/17/2024]
Abstract
Ketone bodies have a negative image because of ketoacidosis, one of the acute and serious complications in diabetes. The negative image persists despite the fact that ketone bodies are physiologically produced in the liver and serve as an indispensable energy source in extrahepatic organs, particularly during long-term fasting. However, accumulating experimental evidence suggests that ketone bodies exert various health benefits. Particularly in the field of aging research, there is growing interest in the potential organoprotective effects of ketone bodies. In addition, ketone bodies have a potential role in preventing kidney diseases, including diabetic kidney disease (DKD), a diabetic complication caused by prolonged hyperglycemia that leads to a decline in kidney function. Ketone bodies may help alleviate the renal burden from hyperglycemia by being used as an alternative energy source in patients with diabetes. Furthermore, ketone body production may reduce inflammation and delay the progression of several kidney diseases in addition to DKD. Although there is still insufficient research on the use of ketone bodies as a treatment and their effects, their renoprotective effects are being gradually proven. This review outlines the ketone body-mediated renoprotective effects in DKD and other kidney diseases.
Collapse
Affiliation(s)
- Kosuke Yamahara
- Department of Medicine, Shiga University of Medical Science, Otsu, Japan
| | | | | | | | | |
Collapse
|
|
15
|
Djaziri N, Burel C, Abbad L, Bakey Z, Piedagnel R, Lelongt B. Cleavage of periostin by MMP9 protects mice from kidney cystic disease. PLoS One 2023; 18:e0294922. [PMID: 38039285 PMCID: PMC10691688 DOI: 10.1371/journal.pone.0294922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 11/12/2023] [Indexed: 12/03/2023] Open
Abstract
The matrix metalloproteinase MMP9 influences cellular morphology and function, and plays important roles in organogenesis and disease. It exerts both protective and deleterious effects in renal pathology, depending upon its specific substrates. To explore new functions for MMP9 in kidney cysts formation and disease progression, we generated a mouse model by breeding juvenile cystic kidney (jck) mice with MMP9 deficient mice. Specifically, we provide evidence that MMP9 is overexpressed in cystic tissue where its enzymatic activity is increased 7-fold. MMP9 deficiency in cystic kidney worsen cystic kidney diseases by decreasing renal function, favoring cyst expansion and fibrosis. In addition, we find that periostin is a new critical substrate for MMP9 and in its absence periostin accumulates in cystic lining cells. As periostin promotes renal cyst growth and interstitial fibrosis in polycystic kidney diseases, we propose that the control of periostin by MMP9 and its associated intracellular signaling pathways including integrins, integrin-linked kinase and focal adhesion kinase confers to MMP9 a protective effect on the severity of the disease.
Collapse
Affiliation(s)
- Nabila Djaziri
- Sorbonne Université, Paris, France
- Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR), Paris, France
| | - Cindy Burel
- Sorbonne Université, Paris, France
- Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR), Paris, France
| | - Lilia Abbad
- Sorbonne Université, Paris, France
- Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR), Paris, France
| | - Zeineb Bakey
- Sorbonne Université, Paris, France
- Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR), Paris, France
| | - Rémi Piedagnel
- Sorbonne Université, Paris, France
- Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR), Paris, France
| | - Brigitte Lelongt
- Sorbonne Université, Paris, France
- Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR), Paris, France
| |
Collapse
|
|
16
|
Dubaic M, Peskova L, Hampl M, Weissova K, Celiker C, Shylo NA, Hruba E, Kavkova M, Zikmund T, Weatherbee SD, Kaiser J, Barta T, Buchtova M. Role of ciliopathy protein TMEM107 in eye development: insights from a mouse model and retinal organoid. Life Sci Alliance 2023; 6:e202302073. [PMID: 37863656 PMCID: PMC10589122 DOI: 10.26508/lsa.202302073] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 09/27/2023] [Accepted: 09/28/2023] [Indexed: 10/22/2023] Open
Abstract
Primary cilia are cellular surface projections enriched in receptors and signaling molecules, acting as signaling hubs that respond to stimuli. Malfunctions in primary cilia have been linked to human diseases, including retinopathies and ocular defects. Here, we focus on TMEM107, a protein localized to the transition zone of primary cilia. TMEM107 mutations were found in patients with Joubert and Meckel-Gruber syndromes. A mouse model lacking Tmem107 exhibited eye defects such as anophthalmia and microphthalmia, affecting retina differentiation. Tmem107 expression during prenatal mouse development correlated with phenotype occurrence, with enhanced expression in differentiating retina and optic stalk. TMEM107 deficiency in retinal organoids resulted in the loss of primary cilia, down-regulation of retina-specific genes, and cyst formation. Knocking out TMEM107 in human ARPE-19 cells prevented primary cilia formation and impaired response to Smoothened agonist treatment because of ectopic activation of the SHH pathway. Our data suggest TMEM107 plays a crucial role in early vertebrate eye development and ciliogenesis in the differentiating retina.
Collapse
Affiliation(s)
- Marija Dubaic
- Laboratory of Molecular Morphogenesis, Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Brno, Czech Republic
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Lucie Peskova
- Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Marek Hampl
- Laboratory of Molecular Morphogenesis, Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Brno, Czech Republic
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Kamila Weissova
- Laboratory of Molecular Morphogenesis, Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Brno, Czech Republic
- Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Canan Celiker
- Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Natalia A Shylo
- Department of Genetics, Yale University, School of Medicine, New Haven, CT, USA
- Stowers Institute for Medical Research, Kansas City, MO, USA
| | - Eva Hruba
- Laboratory of Molecular Morphogenesis, Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Brno, Czech Republic
| | - Michaela Kavkova
- CEITEC - Central European Institute of Technology, Brno University of Technology, Brno, Czech Republic
| | - Tomas Zikmund
- CEITEC - Central European Institute of Technology, Brno University of Technology, Brno, Czech Republic
| | - Scott D Weatherbee
- Department of Genetics, Yale University, School of Medicine, New Haven, CT, USA
- Biology Department, Fairfield University, Fairfield, CT, USA
| | - Jozef Kaiser
- CEITEC - Central European Institute of Technology, Brno University of Technology, Brno, Czech Republic
| | - Tomas Barta
- Laboratory of Molecular Morphogenesis, Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Brno, Czech Republic
- Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Marcela Buchtova
- Laboratory of Molecular Morphogenesis, Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Brno, Czech Republic
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
| |
Collapse
|
|
17
|
Bingol H, Yildirim M, Yildirim K, Alatas B. Automatic classification of kidney CT images with relief based novel hybrid deep model. PeerJ Comput Sci 2023; 9:e1717. [PMID: 38077564 PMCID: PMC10703024 DOI: 10.7717/peerj-cs.1717] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 11/02/2023] [Indexed: 11/04/2024]
Abstract
One of the most crucial organs in the human body is the kidney. Usually, the patient does not realize the serious problems that arise in the kidneys in the early stages of the disease. Many kidney diseases can be detected and diagnosed by specialists with the help of routine computer tomography (CT) images. Early detection of kidney diseases is extremely important for the success of the treatment of the disease and for the prevention of other serious diseases. In this study, CT images of kidneys containing stones, tumors, and cysts were classified using the proposed hybrid model. Results were also obtained using pre-trained models that had been acknowledged in the literature to evaluate the effectiveness of the suggested model. The proposed model consists of 29 layers. While classifying kidney CT images, feature maps were obtained from the convolution 6 and convolution 7 layers of the proposed model, and these feature maps were combined after optimizing with the Relief method. The wide neural network classifier then classifies the optimized feature map. While the highest accuracy value obtained in eight different pre-trained models was 87.75%, this accuracy value was 99.37% in the proposed model. In addition, different performance evaluation metrics were used to measure the performance of the model. These values show that the proposed model has reached high-performance values. Therefore, the proposed approach seems promising in order to automatically and effectively classify kidney CT images.
Collapse
Affiliation(s)
- Harun Bingol
- Software Engineering, Malatya Turgut Ozal University, Malatya, Turkey
| | - Muhammed Yildirim
- Computer Engineering, Malatya Turgut Ozal University, Malatya, Turkey
| | | | - Bilal Alatas
- Software Engineering, Firat (Euphrates) University, Elazig, Turkey
| |
Collapse
|
|
18
|
Li X, Li W, Li Y, Dong C, Zhu P. The safety and efficacy of tolvaptan in the treatment of patients with autosomal dominant polycystic kidney disease: A systematic review and meta-analysis. Nefrologia 2023; 43:731-741. [PMID: 37150675 DOI: 10.1016/j.nefroe.2023.04.002] [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: 05/08/2022] [Accepted: 10/06/2022] [Indexed: 05/09/2023] Open
Abstract
BACKGROUND The irreversible progression of autosomal dominant polycystic kidney disease (ADPKD) to end-stage renal disease (ESRD) is delayed by tolvaptan. Therefore, we aim to systematically estimate and evaluate the efficacy and safety of tolvaptan in the treatment of ADPKD. METHODS Two reviewers independently searched all published randomized controlled trials studies in PubMed, EMBASE, Web of Science and Cochrane databases, extracted data, assessed bias risk and rated the quality of evidence. Data were analyzed by the RevMan software. RESULTS We identified 8 trials including 2135 patients. Both of the decline of estimated glomerular filtration rate (eGFR) [MD=1.89, 95% CI (0.74, 3.04), P=0.001] and total kidney volume (TKV) [MD=-3.32, 95% CI (-4.57, -2.07), P<0.001] were delayed in tolvaptan group compared with placebo group in ADPKD patients. The use of tolvaptan delayed TKV progression in the different-month subgroups [MD=-69.99, 95% CI (-91.05, -48.94), P<0.001]. Tolvaptan reduced renal pain [RR=0.66, 95% CI (0.54, 0.81), P<0.001] and hematuria events [RR=0.55, 95% CI (0.41, 0.74), P<0.001] in ADPKD patients. However, the prevalence of thirst [RR=2.75, 95% CI (2.34, 3.24), P<0.001] and nocturia events [RR=3.01, 95% CI (1.27, 7.11), P=0.01] were increased in tolvaptan group. There is no significant difference of hypertension events [RR=0.92, 95% CI (0.82, 1.03), P=0.13] in tolvaptan group compared placebo group. CONCLUSIONS This meta-analysis suggests that tolvaptan may improve clinical progression in patients with ADPKD without significantly increasing the risk of adverse reactions.
Collapse
Affiliation(s)
- Xuanwei Li
- Division of Nephrology, The First College of Clinical Medical Science, Three Gorges University, Yichang, Hubei, China
| | - Wenlai Li
- Division of Nephrology, The First College of Clinical Medical Science, Three Gorges University, Yichang, Hubei, China
| | - Yue Li
- Division of Endocrinology, The Renhe Hospital of Three Gorges University, Yichang, Hubei, China
| | - Chuanjiang Dong
- Division of Urinary Surgery, The First College of Clinical Medical Science, Three Gorges University , Yichang, Hubei, China
| | - Ping Zhu
- Division of Nephrology, The First College of Clinical Medical Science, Three Gorges University, Yichang, Hubei, China.
| |
Collapse
|
|
19
|
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.
Collapse
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.
| |
Collapse
|
|
20
|
Wang X, Zheng R, Liu Z, Qi L, Gu L, Wang X, Zhu S, Zhang M, Jia D, Su Z. Development and Validation of a Nomogram for Renal Survival Prediction in Patients with Autosomal Dominant Polycystic Kidney Disease. KIDNEY DISEASES (BASEL, SWITZERLAND) 2023; 9:398-407. [PMID: 37901714 PMCID: PMC10601962 DOI: 10.1159/000531329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Accepted: 05/23/2023] [Indexed: 10/31/2023]
Abstract
Introduction Due to the wide variation in the prognosis of autosomal dominant polycystic kidney disease (ADPKD), prediction of risk of renal survival in ADPKD patients is a tough challenge. We aimed to establish a nomogram for the prediction of renal survival in ADPKD patients. Methods We conducted a retrospective observational cohort study in 263 patients with ADPKD. The patients were randomly assigned to a training set (N = 198) and a validation set (N = 65), and demographic and statistical data at baseline were collected. The total kidney volume was measured using stereology. A clinical prediction nomogram was developed based on multivariate Cox regression results. The performance and clinical utility of the nomogram were assessed by calibration curves, the concordance index (C-index), and decision curve analysis (DCA). The nomogram was compared with the height-adjusted total kidney volume (htTKV) model by receiver operating characteristic curve analysis and DCA. Results The five independent factors used to construct the nomogram for prognosis prediction were age, htTKV, estimated glomerular filtration rate, hypertension, and hemoglobin. The calibration curve of predicted probabilities against observed renal survival indicated excellent concordance. The model showed very good discrimination with a C-index of 0.91 (0.83-0.99) and an area under the curve of 0.94, which were significantly higher than those of the htTKV model. Similarly, DCA demonstrated that the nomogram had a better net benefit than the htTKV model. Conclusion The risk prediction nomogram, incorporating easily assessable clinical parameters, was effective for the prediction of renal survival in ADPKD patients. It can be a useful clinical adjunct for clinicians to evaluate the prognosis of ADPKD patients and provide individualized decision-making.
Collapse
Affiliation(s)
- Xiaomei Wang
- Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Department of Nephrology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Rui Zheng
- Department of Critical Care Medicine, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Zhende Liu
- Research Center for Intelligent Supercomputing, Zhejiang Laboratory, Hangzhou, China
| | - Ling Qi
- Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Liang Gu
- Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiaoping Wang
- Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Shan Zhu
- Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Mingyue Zhang
- Department of Radiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Danya Jia
- Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zhen Su
- Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| |
Collapse
|
|
21
|
Ateshian GA, Spack KA, Hone JC, Azeloglu EU, Gusella GL. Computational study of biomechanical drivers of renal cystogenesis. Biomech Model Mechanobiol 2023; 22:1113-1127. [PMID: 37024601 PMCID: PMC10524738 DOI: 10.1007/s10237-023-01704-7] [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: 10/25/2022] [Accepted: 02/12/2023] [Indexed: 04/08/2023]
Abstract
Renal cystogenesis is the pathological hallmark of autosomal dominant polycystic kidney disease, caused by PKD1 and PKD2 mutations. The formation of renal cysts is a common manifestation in ciliopathies, a group of syndromic disorders caused by mutation of proteins involved in the assembly and function of the primary cilium. Cystogenesis is caused by the derailment of the renal tubular architecture and tissue deformation that eventually leads to the impairment of kidney function. However, the biomechanical imbalance of cytoskeletal forces that are altered in cells with Pkd1 mutations has never been investigated, and its nature and extent remain unknown. In this computational study, we explored the feasibility of various biomechanical drivers of renal cystogenesis by examining several hypothetical mechanisms that may promote morphogenetic markers of cystogenesis. Our objective was to provide physics-based guidance for our formulation of hypotheses and our design of experimental studies investigating the role of biomechanical disequilibrium in cystogenesis. We employed the finite element method to explore the role of (1) wild-type versus mutant cell elastic modulus; (2) contractile stress magnitude in mutant cells; (3) localization and orientation of contractile stress in mutant cells; and (4) sequence of cell contraction and cell proliferation. Our objective was to identify the factors that produce the characteristic tubular cystic growth. Results showed that cystogenesis occurred only when mutant cells contracted along the apical-basal axis, followed or accompanied by cell proliferation, as long as mutant cells had comparable or lower elastic modulus than wild-type cells, with their contractile stresses being significantly greater than their modulus. Results of these simulations allow us to focus future in vitro and in vivo experimental studies on these factors, helping us formulate physics-based hypotheses for renal tubule cystogenesis.
Collapse
Affiliation(s)
- Gerard A Ateshian
- Department of Mechanical Engineering, Columbia University, New York, NY, USA.
- Department of Biomedical Engineering, Columbia University, New York, NY, USA.
| | - Katherine A Spack
- Department of Biomedical Engineering, Columbia University, New York, NY, USA
| | - James C Hone
- Department of Mechanical Engineering, Columbia University, New York, NY, USA
| | - Evren U Azeloglu
- Department of Medicine, Division of Nephrology, Mount Sinai School of Medicine, New York, NY, USA
- Department of Pharmacological Sciences, Mount Sinai School of Medicine, New York, NY, USA
| | - G Luca Gusella
- Department of Medicine, Division of Nephrology, Mount Sinai School of Medicine, New York, NY, USA
| |
Collapse
|
|
22
|
Prudhomme T, Boissier R, Hevia V, Campi R, Pecoraro A, Breda A, Territo A. Native nephrectomy and arterial embolization of native kidney in autosomal dominant polycystic kidney disease patients: indications, timing and postoperative outcomes. Minerva Urol Nephrol 2023; 75:17-30. [PMID: 36094388 DOI: 10.23736/s2724-6051.22.04972-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
INTRODUCTION Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common causes of a need of renal replacement therapy. The need (elective vs. systematic) and timing of native kidney nephrectomy (before, after or during kidney transplantation) is a matter of debate and alternatives to surgery, mainly transcatheter arterial embolization have been explored. We performed a systematic review to report all available evidence on postintervention outcomes of native nephrectomy and arterial embolization in ADPKD patients. EVIDENCE ACQUISITION A search on Medline, Embase, and Cochrane databases was performed to identify all studies reporting outcomes of native nephrectomy or arterial embolization in APKDs. EVIDENCE SYNTHESIS Concerning native nephrectomy, a total of 3626 patients in 37 studies were included with 735, 210 and 2681 patients who underwent native nephrectomy respectively before, after or during kidney transplantation. Major complications were 12.2% in unilateral nephrectomy before transplantation, 25.0% in bilateral nephrectomy before transplantation, 17.7% in unilateral nephrectomy during transplantation, 20.8% in bilateral nephrectomy during transplantation and 23.8% in unilateral and bilateral nephrectomy after transplantation. A total of 230 patients in 7 series of arterial embolization were included. All arterial embolization were performed before transplantation. Mean volume reduction ranged from 36.3% at 3 months to 49% at 6 months. The major postintervention complication rate was 1%. CONCLUSIONS Unilateral native nephrectomy before kidney transplantation was associated with the lowest major postoperative complication rate and appears to be the preferred strategy. Arterial embolization reduces kidney volume by 49% at 6 months. Arterial embolization could be considered when the reduction in size of the native kidney is not urgent.
Collapse
Affiliation(s)
- Thomas Prudhomme
- Department of Urology, Rangueil University Hospital, Toulouse, France -
| | - Romain Boissier
- Department of Urology, La Conception University Hospital, Marseille, France
| | - Vital Hevia
- Department of Urology, University Hospital Ramón y Cajal, Madrid, Spain
| | - Riccardo Campi
- Department of Urology, University Hospital of Florence, Florence, Italy
| | - Alessio Pecoraro
- Department of Urology, University Hospital of Florence, Florence, Italy
| | - Alberto Breda
- Unit of Oncology and Renal Transplant, Puigvert's Foundation, Barcelona, Spain
| | - Angelo Territo
- Unit of Oncology and Renal Transplant, Puigvert's Foundation, Barcelona, Spain
| | | |
Collapse
|
|
23
|
Price ME, Fishler KP, Muff-Luett M, Mauch TJ, Brunelli L, Euteneuer JC. Variants in AQP11 may result in autosomal recessive bilateral cystic renal dysgenesis. Am J Med Genet A 2023; 191:612-616. [PMID: 36420936 DOI: 10.1002/ajmg.a.63056] [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: 10/07/2022] [Revised: 11/01/2022] [Accepted: 11/02/2022] [Indexed: 11/25/2022]
Abstract
Congenital renal cystic dysplasia is a rare disease that occurs in approximately 1 in 4000 children and is often discovered in the antenatal period by ultrasound. It is commonly associated with oligohydramnios in utero and/or renal insufficiency or failure in the postnatal period. Aquaporins are membrane proteins that serve as transport channels in the transfer of water or small solutes across cell membranes. They play a role in the development of renal cysts. Aquaporin 11 (AQP11) deficient mice develop polycystic kidney disease in utero due to disruption of polycystin-1. Here we describe a case of bilateral cystic kidney disease in a patient with novel compound heterozygous variants in AQP11: c.780G>T (p. Trp260Cys) and c.472C>T (p.Pro158Ser) (NM_173039.2) identified by whole genome sequencing. These findings suggest, for the first time, the potential role of AQP11 in congenital renal cystic dysplasia.
Collapse
Affiliation(s)
- Michael E Price
- University of Nebraska Medical Center, College of Medicine, Omaha, Nebraska, USA
| | - Kristen P Fishler
- Munroe-Meyer Institute of Genetics and Rehabilitation, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Melissa Muff-Luett
- Department of Pediatrics, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Teri J Mauch
- Department of Pediatrics, University of Nebraska Medical Center, Omaha, Nebraska, USA.,Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA
| | - Luca Brunelli
- Department of Pediatrics, University of Nebraska Medical Center, Omaha, Nebraska, USA.,Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA
| | - Joshua C Euteneuer
- Department of Pediatrics, University of Nebraska Medical Center, Omaha, Nebraska, USA
| |
Collapse
|
|
24
|
Klawitter J, Jackson MJ, Smith PH, Hopp K, Chonchol M, Gitomer BY, Cadnapaphornchai MA, Christians U, Klawitter J. Kynurenines in polycystic kidney disease. J Nephrol 2023; 36:83-91. [PMID: 35867237 PMCID: PMC9867782 DOI: 10.1007/s40620-022-01361-6] [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: 01/20/2022] [Accepted: 05/19/2022] [Indexed: 02/06/2023]
Abstract
BACKGROUND Autosomal dominant polycystic kidney disease (ADPKD) is a common hereditary disorder, characterized by kidney cyst formation. A major pathological feature of ADPKD is the development of interstitial inflammation. Due to its role in inflammation and oxidative stress, tryptophan metabolism and related kynurenines may have relevance in ADPKD. METHODS Data were collected from a well-characterized longitudinal cohort of pediatric and adult patients with ADPKD and compared to age-matched healthy subjects. To evaluate the role of kynurenines in ADPKD severity and progression, we investigated their association with height-corrected total kidney volume (HtTKV) and kidney function (estimated glomerular filtration rate (eGFR)). Key tryptophan metabolites were measured in plasma using a validated liquid chromatography-mass spectrometry assay. RESULTS There was a significant accumulation of kynurenine and kynurenic acid (KYNA) in children and adults with ADPKD as compared to healthy subjects. Downstream kynurenines continued to accumulate in adults with ADPKD concurrent with the increase of inflammatory markers IL-6 and MCP-1. Both markers remained unchanged in ADPKD as compared to healthy children, suggesting alternate pathways responsible for the observed rise in kynurenine and KYNA. KYNA and kynurenine/tryptophan positively associated with disease severity (HtTKV or eGFR) in patients with ADPKD. After Bonferroni adjustment, baseline kynurenines did not associate with disease progression (yearly %change in HtTKV or yearly change in eGFR) in this limited number of patients with ADPKD. CONCLUSION Kynurenine metabolism seems dysregulated in ADPKD as compared to healthy subjects. Inhibition of kynurenine production by inhibition of main pathway enzymes could present a novel way to reduce the progression of ADPKD.
Collapse
Affiliation(s)
- Jost Klawitter
- Department of Anesthesiology, University of Colorado School of Medicine, University of Colorado Denver Anschutz Medical Campus, 12705 E Montview Blvd, Bioscience 2, Suite 200, Aurora, CO, 80045-7109, USA
| | - Matthew J Jackson
- Department of Anesthesiology, University of Colorado School of Medicine, University of Colorado Denver Anschutz Medical Campus, 12705 E Montview Blvd, Bioscience 2, Suite 200, Aurora, CO, 80045-7109, USA
| | - Peter H Smith
- Department of Anesthesiology, University of Colorado School of Medicine, University of Colorado Denver Anschutz Medical Campus, 12705 E Montview Blvd, Bioscience 2, Suite 200, Aurora, CO, 80045-7109, USA
| | - Katharina Hopp
- Division of Renal Diseases and Hypertension, University of Colorado School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Michel Chonchol
- Division of Renal Diseases and Hypertension, University of Colorado School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Berenice Y Gitomer
- Division of Renal Diseases and Hypertension, University of Colorado School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Melissa A Cadnapaphornchai
- Division of Renal Diseases and Hypertension, University of Colorado School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Presbyterian/St. Luke's Medical Center, Denver, CO, USA
| | - Uwe Christians
- Department of Anesthesiology, University of Colorado School of Medicine, University of Colorado Denver Anschutz Medical Campus, 12705 E Montview Blvd, Bioscience 2, Suite 200, Aurora, CO, 80045-7109, USA
| | - Jelena Klawitter
- Department of Anesthesiology, University of Colorado School of Medicine, University of Colorado Denver Anschutz Medical Campus, 12705 E Montview Blvd, Bioscience 2, Suite 200, Aurora, CO, 80045-7109, USA.
- Division of Renal Diseases and Hypertension, University of Colorado School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
| |
Collapse
|
|
25
|
Espinosa Cabello M, Ansio Vázquez I, Espejo Portero I, Rodriguez Fuentes D, Rabasco Ruiz C, Espinosa Hernández M. The natural history of autosomal dominant polycystic kidney disease. A strategy for grouping families and mutations. Nefrologia 2023; 43:120-125. [PMID: 37268502 DOI: 10.1016/j.nefroe.2023.03.010] [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: 12/20/2021] [Accepted: 05/17/2022] [Indexed: 06/04/2023] Open
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is a main cause of end-stage renal disease. Today, knowledge of its genetic basis has made it possible to develop strategies that prevent the transmission of the disease. OBJECTIVES The objective of the study was to analyze the natural history of ADPKD in the province of Córdoba and to design a database that allows grouping families with different mutations. PATIENTS AND METHODS All patients (n = 678) diagnosed with ADPKD followed by the Córdoba nephrology service are included. Various clinical variables (age and sex), genetic variables (mutation in PKD1, PKD2) and the need for renal replacement therapy (RRT) were retrospectively analyzed. RESULTS The prevalence was 61 cases per 100,000 inhabitants. Median renal survival was significantly worse in PKD1 (57.5 years) than in PKD2 (70 years) (log-rank p = 0.000). We have genetically identified 43.8% of the population, detecting PKD1 mutations in 61.2% and PKD2 mutations in 37.4% of cases, respectively. The most frequent mutation, in PKD2 (c.2159del), appeared in 68 patients belonging to 10 different families. The one with the worst renal prognosis was a truncating mutation in PKD1 (c.9893 G > A). These patients required RRT at a median age of 38.7 years. CONCLUSIONS Renal survival of ADPKD in the province of Córdoba is similar to that described in the literature. We detected PKD2 mutations in 37.4% of cases. This strategy allows us to know the genetic basis of a large proportion of our population while saving resources. This is essential to be able to offer primary prevention of ADPKD through preimplantation genetic diagnosis.
Collapse
Affiliation(s)
| | | | - Isabel Espejo Portero
- UGC de Análisis Clínicos, Genética-Molecular, Hospital Universitario Reina Sofía. Córdoba, Spain
| | | | | | | |
Collapse
|
|
26
|
Glucose absorption drives cystogenesis in a human organoid-on-chip model of polycystic kidney disease. Nat Commun 2022; 13:7918. [PMID: 36564419 PMCID: PMC9789147 DOI: 10.1038/s41467-022-35537-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Accepted: 12/08/2022] [Indexed: 12/24/2022] Open
Abstract
In polycystic kidney disease (PKD), fluid-filled cysts arise from tubules in kidneys and other organs. Human kidney organoids can reconstitute PKD cystogenesis in a genetically specific way, but the mechanisms underlying cystogenesis remain elusive. Here we show that subjecting organoids to fluid shear stress in a PKD-on-a-chip microphysiological system promotes cyst expansion via an absorptive rather than a secretory pathway. A diffusive static condition partially substitutes for fluid flow, implicating volume and solute concentration as key mediators of this effect. Surprisingly, cyst-lining epithelia in organoids polarize outwards towards the media, arguing against a secretory mechanism. Rather, cyst formation is driven by glucose transport into lumens of outwards-facing epithelia, which can be blocked pharmacologically. In PKD mice, glucose is imported through cysts into the renal interstitium, which detaches from tubules to license expansion. Thus, absorption can mediate PKD cyst growth in human organoids, with implications for disease mechanism and potential for therapy development.
Collapse
|
|
27
|
Seeman T, Bláhová K, Fencl F, Klaus R, Lange-Sperandio B, Hrčková G, Podracká Ĺ. Kidney concentrating capacity in children with autosomal recessive polycystic kidney disease is linked to glomerular filtration and hypertension. Pediatr Nephrol 2022:10.1007/s00467-022-05834-5. [PMID: 36538056 DOI: 10.1007/s00467-022-05834-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 11/16/2022] [Accepted: 11/16/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND Impaired kidney concentration capacity is present in half of the patients with autosomal dominant polycystic kidney disease (ADPKD). The kidney concentrating capacity was further impaired within the animal model of autosomal recessive polycystic kidney disease (ARPKD). To date, only one small study has investigated it in children having ARPKD. Therefore, we aimed to study the kidney concentrating ability in a larger cohort of children with ARPKD. METHODS Eighteen children (median age 8.5 years, range 1.3-16.8) were retrospectively investigated. A standardized kidney concentrating capacity test was performed after the application of a nasal drop of desmopressin (urine osmolality > 900 mOsmol/kg). The glomerular filtration rate was estimated using the Schwartz formula (eGFR) and blood pressure (BP) was measured as office BP. RESULTS Kidney concentrating capacity was decreased (urine osmolality < 900 mOsmol/kg) in 100% of children with ARPKD. The median urine osmolality after desmopressin application was 389 (range 235-601) mOsmol/kg. Sixteen patients (89%) were defined as hypertensive based on their actual BP level or their use of antihypertensive drugs. The maximum amounts of urinary concentration correlated significantly with eGFR (r = 0.72, p < 0.0001) and hypertensive scores (r = 0.50, p < 0.05), but not with kidney size. Twelve patients (67%) were defined as having CKD stages 2-4. The median concentrating capacity was significantly lower in children within this group, when compared to children with CKD stage 1 possessing a normal eGFR (544 mOsmol/kg, range 413-600 mOsmol/kg vs. 327 mOsmol/kg, range 235-417 mOsmol/l, p < 0.001). CONCLUSIONS Impaired kidney concentrating capacity is present in most children with ARPKD and is associated with decreased eGFR and hypertension. A higher resolution version of the Graphical abstract is available as Supplementary information.
Collapse
Affiliation(s)
- Tomáš Seeman
- Department of Pediatrics, Dr. v. Hauner Children's Hospital, University Hospital, Ludwig Maximilian University Munich, Lindwurmstraße 4, 80337, Munich, Germany.
- Department of Pediatrics, 2nd Medical Faculty, Charles University, Prague, Czech Republic.
- Department of Pediatrics, University Hospital Ostrava, Ostrava, Czech Republic.
| | - Kveta Bláhová
- Department of Pediatrics, 2nd Medical Faculty, Charles University, Prague, Czech Republic
| | - Filip Fencl
- Department of Pediatrics, 2nd Medical Faculty, Charles University, Prague, Czech Republic
| | - Richard Klaus
- Department of Pediatrics, Dr. v. Hauner Children's Hospital, University Hospital, Ludwig Maximilian University Munich, Lindwurmstraße 4, 80337, Munich, Germany
- Department of Pediatrics, 2nd Medical Faculty, Charles University, Prague, Czech Republic
| | - Bärbel Lange-Sperandio
- Department of Pediatrics, Dr. v. Hauner Children's Hospital, University Hospital, Ludwig Maximilian University Munich, Lindwurmstraße 4, 80337, Munich, Germany
| | - Gabriela Hrčková
- Department of Pediatrics, Medical Faculty, Comenius University and National Institute of Children's Diseases, Bratislava, Slovakia
| | - Ĺudmila Podracká
- Department of Pediatrics, Medical Faculty, Comenius University and National Institute of Children's Diseases, Bratislava, Slovakia
| |
Collapse
|
|
28
|
Abstract
The most severe forms of congenital anomalies of the kidney and urinary tract present in fetal life with early pregnancy renal anhydramnios and are considered lethal due to pulmonary hypoplasia without fetal therapy. Due to the high rate of additional structural anomalies, genetic abnormalities, and associated syndromes, detailed anatomic survey and genetic testing are imperative when stratifying which pregnancies are appropriate for fetal intervention. Restoring amniotic fluid around the fetus is the principal goal of prenatal treatment. The ongoing multi-center Renal Anhydramnios Fetal Therapy (RAFT) trial is assessing the safety and efficacy of serial amnioinfusions to prevent pulmonary hypoplasia so that the underlying renal disease can be addressed.
Collapse
|
|
29
|
Kang E, Li Y, Kim B, Huh KY, Han M, Ahn JH, Sung HY, Park YS, Lee SE, Lee S, Park SK, Cho JY, Oh KH. Identification of Serum Metabolites for Predicting Chronic Kidney Disease Progression according to Chronic Kidney Disease Cause. Metabolites 2022; 12:1125. [PMID: 36422264 PMCID: PMC9696352 DOI: 10.3390/metabo12111125] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/03/2022] [Accepted: 11/10/2022] [Indexed: 12/01/2023] Open
Abstract
Early detection and proper management of chronic kidney disease (CKD) can delay progression to end-stage kidney disease. We applied metabolomics to discover novel biomarkers to predict the risk of deterioration in patients with different causes of CKD. We enrolled non-dialytic diabetic nephropathy (DMN, n = 124), hypertensive nephropathy (HTN, n = 118), and polycystic kidney disease (PKD, n = 124) patients from the KNOW-CKD cohort. Within each disease subgroup, subjects were categorized as progressors (P) or non-progressors (NP) based on the median eGFR slope. P and NP pairs were randomly selected after matching for age, sex, and baseline eGFR. Targeted metabolomics was performed to quantify 188 metabolites in the baseline serum samples. We selected ten progression-related biomarkers for DMN and nine biomarkers each for HTN and PKD. Clinical parameters showed good ability to predict DMN (AUC 0.734); however, this tendency was not evident for HTN (AUC 0.659) or PKD (AUC 0.560). Models constructed with selected metabolites and clinical parameters had better ability to predict CKD progression than clinical parameters only. When selected metabolites were used in combination with clinical indicators, random forest prediction models for CKD progression were constructed with AUCs of 0.826, 0.872, and 0.834 for DMN, HTN, and PKD, respectively. Select novel metabolites identified in this study can help identify high-risk CKD patients who may benefit from more aggressive medical treatment.
Collapse
Grants
- 2011E3300300, 2012E3301100, 2013E3301600, 2013E3301601, 2013E3301602, 2016E3300200, 2016E3300201, 2016E3300202, 2019E320100, 2019E320101, 2019E320102, and 2022-11-007 Korea Disease Control and Prevention Agency
- 2017M3A9E4044649 the Korean government (MSIT)
Collapse
Affiliation(s)
- Eunjeong Kang
- Department of Internal Medicine, Ewha Womans University Seoul Hospital, Ewha Womans University College of Medicine, Seoul 07804, Republic of Korea
| | - Yufei Li
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul 03080, Republic of Korea
| | - Bora Kim
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul 03080, Republic of Korea
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Ki Young Huh
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul 03080, Republic of Korea
| | - Miyeun Han
- Department of Internal Medicine, National Medical Center, Seoul 04564, Republic of Korea
| | - Jung-Hyuck Ahn
- Department of Biochemistry, Ewha Womans University College of Medicine, Seoul 07804, Republic of Korea
| | - Hye Youn Sung
- Department of Biochemistry, Ewha Womans University College of Medicine, Seoul 07804, Republic of Korea
| | - Yong Seek Park
- Department of Microbiology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Seung Eun Lee
- Department of Microbiology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Sangjun Lee
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul 03080, Republic of Korea
| | - Sue K. Park
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
- Integrated Major in Innovative Medical Science, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Joo-Youn Cho
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul 03080, Republic of Korea
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul 03080, Republic of Korea
| | - Kook-Hwan Oh
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| |
Collapse
|
|
30
|
Xu Y, Kuppe C, Perales-Patón J, Hayat S, Kranz J, Abdallah AT, Nagai J, Li Z, Peisker F, Saritas T, Halder M, Menzel S, Hoeft K, Kenter A, Kim H, van Roeyen CRC, Lehrke M, Moellmann J, Speer T, Buhl EM, Hoogenboezem R, Boor P, Jansen J, Knopp C, Kurth I, Smeets B, Bindels E, Reinders MEJ, Baan C, Gribnau J, Hoorn EJ, Steffens J, Huber TB, Costa I, Floege J, Schneider RK, Saez-Rodriguez J, Freedman BS, Kramann R. Adult human kidney organoids originate from CD24 + cells and represent an advanced model for adult polycystic kidney disease. Nat Genet 2022; 54:1690-1701. [PMID: 36303074 PMCID: PMC7613830 DOI: 10.1038/s41588-022-01202-z] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 09/09/2022] [Indexed: 11/09/2022]
Abstract
Adult kidney organoids have been described as strictly tubular epithelia and termed tubuloids. While the cellular origin of tubuloids has remained elusive, here we report that they originate from a distinct CD24+ epithelial subpopulation. Long-term-cultured CD24+ cell-derived tubuloids represent a functional human kidney tubule. We show that kidney tubuloids can be used to model the most common inherited kidney disease, namely autosomal dominant polycystic kidney disease (ADPKD), reconstituting the phenotypic hallmark of this disease with cyst formation. Single-cell RNA sequencing of CRISPR-Cas9 gene-edited PKD1- and PKD2-knockout tubuloids and human ADPKD and control tissue shows similarities in upregulation of disease-driving genes. Furthermore, in a proof of concept, we demonstrate that tolvaptan, the only approved drug for ADPKD, has a significant effect on cyst size in tubuloids but no effect on a pluripotent stem cell-derived model. Thus, tubuloids are derived from a tubular epithelial subpopulation and represent an advanced system for ADPKD disease modeling.
Collapse
Affiliation(s)
- Yaoxian Xu
- Institute of Experimental Medicine and Systems Biology, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Christoph Kuppe
- Institute of Experimental Medicine and Systems Biology, Medical Faculty, RWTH Aachen University, Aachen, Germany
- Division of Nephrology and Clinical Immunology, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Javier Perales-Patón
- Institute of Experimental Medicine and Systems Biology, Medical Faculty, RWTH Aachen University, Aachen, Germany
- Institute for Computational Biomedicine, Faculty of Medicine, Heidelberg University and Heidelberg University Hospital, Bioquant, Heidelberg, Germany
| | - Sikander Hayat
- Institute of Experimental Medicine and Systems Biology, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Jennifer Kranz
- Institute of Experimental Medicine and Systems Biology, Medical Faculty, RWTH Aachen University, Aachen, Germany
- Department of Urology and Pediatric Urology, RWTH Aachen University, Aachen, Germany
- Department of Urology and Kidney Transplantation, Martin-Luther-University, Halle, Germany
| | - Ali T Abdallah
- Interdisciplinary Center for Clinical Research, RWTH Aachen University, Aachen, Germany
| | - James Nagai
- Institute of Computational Genomics, RWTH Aachen University, Aachen, Germany
| | - Zhijian Li
- Institute of Computational Genomics, RWTH Aachen University, Aachen, Germany
| | - Fabian Peisker
- Institute of Experimental Medicine and Systems Biology, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Turgay Saritas
- Institute of Experimental Medicine and Systems Biology, Medical Faculty, RWTH Aachen University, Aachen, Germany
- Division of Nephrology and Clinical Immunology, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Maurice Halder
- Institute of Experimental Medicine and Systems Biology, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Sylvia Menzel
- Institute of Experimental Medicine and Systems Biology, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Konrad Hoeft
- Institute of Experimental Medicine and Systems Biology, Medical Faculty, RWTH Aachen University, Aachen, Germany
- Division of Nephrology and Clinical Immunology, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Annegien Kenter
- Department of Developmental Biology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
- Department of Cell Biology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
- Department of Internal Medicine and Department of Nephrology and Transplantation, Erasmus Medical Center Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Hyojin Kim
- Institute of Experimental Medicine and Systems Biology, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Claudia R C van Roeyen
- Institute of Experimental Medicine and Systems Biology, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Michael Lehrke
- Department of Cardiology, RWTH Aachen University, Aachen, Germany
| | - Julia Moellmann
- Department of Cardiology, RWTH Aachen University, Aachen, Germany
| | - Thimoteus Speer
- Department of Nephrology, University Hospital Homburg, Homburg, Germany
| | - Eva M Buhl
- Institute of Pathology and Electron Microscopy Facility, RWTH Aachen University, Aachen, Germany
| | - Remco Hoogenboezem
- Department of Hematology, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Peter Boor
- Division of Nephrology and Clinical Immunology, Medical Faculty, RWTH Aachen University, Aachen, Germany
- Institute of Pathology and Electron Microscopy Facility, RWTH Aachen University, Aachen, Germany
| | - Jitske Jansen
- Institute of Experimental Medicine and Systems Biology, Medical Faculty, RWTH Aachen University, Aachen, Germany
- Department of Pathology, RIMLS, Radboudumc, Nijmegen, the Netherlands
| | - Cordula Knopp
- Institute of Human Genetics, RWTH Aachen University, Aachen, Germany
| | - Ingo Kurth
- Institute of Human Genetics, RWTH Aachen University, Aachen, Germany
| | - Bart Smeets
- Department of Pathology, RIMLS, Radboudumc, Nijmegen, the Netherlands
| | - Eric Bindels
- Department of Hematology, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Marlies E J Reinders
- Department of Internal Medicine and Department of Nephrology and Transplantation, Erasmus Medical Center Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Carla Baan
- Department of Internal Medicine and Department of Nephrology and Transplantation, Erasmus Medical Center Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Joost Gribnau
- Department of Developmental Biology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
- Department of Cell Biology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Ewout J Hoorn
- Department of Internal Medicine and Department of Nephrology and Transplantation, Erasmus Medical Center Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Joachim Steffens
- Department of Urology, St Antonius Hospital, Eschweiler, Germany
| | - Tobias B Huber
- III Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ivan Costa
- Institute of Computational Genomics, RWTH Aachen University, Aachen, Germany
| | - Jürgen Floege
- Division of Nephrology and Clinical Immunology, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Rebekka K Schneider
- Department of Developmental Biology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
- Institute of Cell and Tumor Biology, RWTH Aachen University, Aachen, Germany
| | - Julio Saez-Rodriguez
- Institute for Computational Biomedicine, Faculty of Medicine, Heidelberg University and Heidelberg University Hospital, Bioquant, Heidelberg, Germany
- Joint Research Center for Computational Biomedicine, RWTH Aachen University, Aachen, Germany
- Molecular Medicine Partnership Unit (MMPU), European Molecular Biology Laboratory and Heidelberg University, Heidelberg, Germany
| | - Benjamin S Freedman
- Department of Medicine, Division of Nephrology, Kidney Research Institute and Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA
- Department of Bioengineering (Adjunct), and Department of Laboratory Medicine & Pathology (Adjunct), University of Washington, Seattle, WA, USA
| | - Rafael Kramann
- Institute of Experimental Medicine and Systems Biology, Medical Faculty, RWTH Aachen University, Aachen, Germany.
- Division of Nephrology and Clinical Immunology, Medical Faculty, RWTH Aachen University, Aachen, Germany.
- Department of Internal Medicine and Department of Nephrology and Transplantation, Erasmus Medical Center Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands.
| |
Collapse
|
|
31
|
Muto Y, Dixon EE, Yoshimura Y, Wu H, Omachi K, Ledru N, Wilson PC, King AJ, Eric Olson N, Gunawan MG, Kuo JJ, Cox JH, Miner JH, Seliger SL, Woodward OM, Welling PA, Watnick TJ, Humphreys BD. Defining cellular complexity in human autosomal dominant polycystic kidney disease by multimodal single cell analysis. Nat Commun 2022; 13:6497. [PMID: 36310237 PMCID: PMC9618568 DOI: 10.1038/s41467-022-34255-z] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 10/17/2022] [Indexed: 12/25/2022] Open
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is the leading genetic cause of end stage renal disease characterized by progressive expansion of kidney cysts. To better understand the cell types and states driving ADPKD progression, we analyze eight ADPKD and five healthy human kidney samples, generating single cell multiomic atlas consisting of ~100,000 single nucleus transcriptomes and ~50,000 single nucleus epigenomes. Activation of proinflammatory, profibrotic signaling pathways are driven by proximal tubular cells with a failed repair transcriptomic signature, proinflammatory fibroblasts and collecting duct cells. We identify GPRC5A as a marker for cyst-lining collecting duct cells that exhibits increased transcription factor binding motif availability for NF-κB, TEAD, CREB and retinoic acid receptors. We identify and validate a distal enhancer regulating GPRC5A expression containing these motifs. This single cell multiomic analysis of human ADPKD reveals previously unrecognized cellular heterogeneity and provides a foundation to develop better diagnostic and therapeutic approaches.
Collapse
Affiliation(s)
- Yoshiharu Muto
- Division of Nephrology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA
| | - Eryn E Dixon
- Division of Nephrology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA
| | - Yasuhiro Yoshimura
- Division of Nephrology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA
| | - Haojia Wu
- Division of Nephrology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA
| | - Kohei Omachi
- Division of Nephrology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA
| | - Nicolas Ledru
- Division of Nephrology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA
| | - Parker C Wilson
- Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, USA
| | | | | | | | - Jay J Kuo
- Chinook Therapeutics, Inc., Vancouver, BC, Canada
| | | | - Jeffrey H Miner
- Division of Nephrology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA
| | - Stephen L Seliger
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Owen M Woodward
- Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA
| | | | - Terry J Watnick
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, 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.
| |
Collapse
|
|
32
|
Li X, Li W, Li Y, Dong C, Zhu P. The safety and efficacy of tolvaptan in the treatment of patients with autosomal dominant polycystic kidney disease: A systematic review and meta-analysis. Nefrologia 2022. [DOI: 10.1016/j.nefro.2022.10.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
|
|
33
|
Coussy A, Jambon E, Le Bras Y, Combe C, Chiche L, Grenier N, Marcelin C. The Safety and Efficacy of Hepatic Transarterial Embolization Using Microspheres and Microcoils in Patients with Symptomatic Polycystic Liver Disease. J Pers Med 2022; 12:jpm12101624. [PMID: 36294764 PMCID: PMC9605116 DOI: 10.3390/jpm12101624] [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: 08/08/2022] [Revised: 09/06/2022] [Accepted: 09/11/2022] [Indexed: 11/06/2022] Open
Abstract
Purpose: We investigated the long-term safety and efficacy of hepatic transarterial embolization (TAE) in patients with symptomatic polycystic liver disease (PLD). Materials and Methods: A total of 26 patients were included, mean age of 52.3 years (range: 33−78 years), undergoing 32 TAE procedures between January 2012 and December 2019 were included in this retrospective study. Distal embolization of the segmental hepatic artery was performed with 300−500 µm embolic microspheres associated with proximal embolization using microcoils. The primary endpoint was clinical efficacy, defined by an improvement in health-related quality of life using a modified Short Form-36 Health Survey and improvement in symptoms (digestive or respiratory symptoms and chronic abdominal pain), without invasive therapy during the follow-up period. Secondary endpoints were a decrease in total liver volume and treated liver volume and complications. Results: Hepatic embolization was performed successfully in 30 of 32 procedures with no major adverse events. Clinical efficacy was 73% (19/26). The mean reduction in hepatic volume was −12.6% at 3 months and −27.8% at the last follow-up 51 ± 15.2 months after TAE (range: 30−81 months; both ps < 0.01). The mean visual analog scale pain score was 5.4 ± 2.8 before TAE and decreased to 2.7 ± 1.9 after treatment. Three patients had minor adverse events, and one patient had an adverse event of moderate severity. Conclusion: Hepatic embolization using microspheres and microcoils is a safe and effective treatment for PLD that improves symptoms and reduces the volume of hepatic cysts.
Collapse
Affiliation(s)
- Alexis Coussy
- Department of Radiology, Pellegrin Hospital, Place Amélie Raba Léon, 33076 Bordeaux, France
| | - Eva Jambon
- Department of Radiology, Pellegrin Hospital, Place Amélie Raba Léon, 33076 Bordeaux, France
| | - Yann Le Bras
- Department of Radiology, Pellegrin Hospital, Place Amélie Raba Léon, 33076 Bordeaux, France
| | - Christian Combe
- Departement of Nephrology, Pellegrin Hospital, Place Amélie Raba Léon, 33076 Bordeaux, France
| | - Laurence Chiche
- Department of Digestive surgery, Haut Leveque, 33076 Bordeaux, France
| | - Nicolas Grenier
- Department of Radiology, Pellegrin Hospital, Place Amélie Raba Léon, 33076 Bordeaux, France
| | - Clément Marcelin
- Department of Radiology, Pellegrin Hospital, Place Amélie Raba Léon, 33076 Bordeaux, France
- Correspondence: ; Tel.: +33-556-795-599; Fax: +33-557-821-650
| |
Collapse
|
|
34
|
Su L, Yuan H, Zhang H, Wang R, Fu K, Yin L, Ren Y, Liu H, Fang Q, Wang J, Guo D. PF-06409577 inhibits renal cyst progression by concurrently inhibiting the mTOR pathway and CFTR channel activity. FEBS Open Bio 2022; 12:1761-1770. [PMID: 35748097 PMCID: PMC9527591 DOI: 10.1002/2211-5463.13459] [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: 03/18/2022] [Revised: 05/31/2022] [Accepted: 06/22/2022] [Indexed: 12/14/2022] Open
Abstract
Renal cyst development and expansion in autosomal dominant polycystic kidney disease (ADPKD) involves over-proliferation of cyst-lining epithelial cells and excessive cystic fluid secretion. While metformin effectively inhibits renal cyst growth in mouse models of ADPKD it exhibits low potency, and thus an adenosine monophosphate-activated protein kinase (AMPK) activator with higher potency is required. Herein, we adopted a drug repurposing strategy to explore the potential of PF-06409577, an AMPK activator for diabetic nephropathy, in cellular, ex vivo and in vivo models of ADPKD. Our results demonstrated that PF-06409577 effectively down-regulated mammalian target of rapamycin pathway-mediated proliferation of cyst-lining epithelial cells and reduced cystic fibrosis transmembrane conductance regulator-regulated cystic fluid secretion. Overall, our data suggest that PF-06409577 holds therapeutic potential for ADPKD treatment.
Collapse
Affiliation(s)
- Limin Su
- Jiangsu Key Laboratory of New Drug Research and Clinical PharmacyXuzhou Medical UniversityChina
| | - Haoxing Yuan
- Jiangsu Key Laboratory of New Drug Research and Clinical PharmacyXuzhou Medical UniversityChina
| | - Haoran Zhang
- Jiangsu Key Laboratory of New Drug Research and Clinical PharmacyXuzhou Medical UniversityChina
| | - Ruoqi Wang
- Jiangsu Key Laboratory of New Drug Research and Clinical PharmacyXuzhou Medical UniversityChina
| | - Kequan Fu
- Jiangsu Key Laboratory of New Drug Research and Clinical PharmacyXuzhou Medical UniversityChina
| | - Long Yin
- Jiangsu Key Laboratory of New Drug Research and Clinical PharmacyXuzhou Medical UniversityChina
| | - Ying Ren
- Jiangsu Key Laboratory of New Drug Research and Clinical PharmacyXuzhou Medical UniversityChina
| | - Hongli Liu
- Jiangsu Key Laboratory of New Drug Research and Clinical PharmacyXuzhou Medical UniversityChina
| | - Qian Fang
- Department of UrologyThe Affiliated Hospital of Xuzhou Medical UniversityChina
| | - Junqi Wang
- Department of UrologyThe Affiliated Hospital of Xuzhou Medical UniversityChina
| | - Dong Guo
- Jiangsu Key Laboratory of New Drug Research and Clinical PharmacyXuzhou Medical UniversityChina
| |
Collapse
|
|
35
|
Historia natural de la poliquistosis renal autosómica dominante en Córdoba: utilidad de una base de datos para agrupar familias y mutaciones. Nefrologia 2022. [DOI: 10.1016/j.nefro.2022.05.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
|
|
36
|
Cortvrindt C, Speeckaert R, Delanghe JR, Speeckaert MM. Urinary Epidermal Growth Factor: A Promising "Next Generation" Biomarker in Kidney Disease. Am J Nephrol 2022; 53:372-387. [PMID: 35537382 DOI: 10.1159/000524586] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Accepted: 04/06/2022] [Indexed: 11/19/2022]
Abstract
BACKGROUND The epidermal growth factor (EGF) is a globular protein that is generated in the kidney, especially in the loop of Henle and the distal convoluted tubule. While EGF is nonexistent or hardly detectable in plasma, it is present in normal people's urine. Until now, risk stratification and chronic kidney disease (CKD) diagnosis have relied on estimated glomerular filtration rate (eGFR) and urine albumin/creatinine ratio (uACR), both of which reflect glomerular function or impairment. Tubular dysfunction, on the other hand, may also be associated with renal failure. SUMMARY Because decreased urine EGF (uEGF) indicates tubular atrophy and interstitial fibrosis, this biomarker, together with eGFR and uACR, may be employed in the general population for risk assessment and diagnosis of CKD. uEGF levels have been shown to correlate with intrarenal EGF mRNA expression and have been found to decrease in a variety of glomerular and non-glomerular kidney disorders. KEY MESSAGE uEGF, uEGF/creatinine, or uEGF/monocyte chemotactic peptide-1 are possible "new generation" biomarkers linked to a variety of kidney diseases that deserve further investigation as a single biomarker or as part of a multi-biomarker panel.
Collapse
Affiliation(s)
| | | | - Joris R Delanghe
- Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
| | - Marijn M Speeckaert
- Department of Nephrology, Ghent University Hospital, Ghent, Belgium
- Research Foundation-Flanders (FWO), Brussels, Belgium
| |
Collapse
|
|
37
|
Ziegler WH, Lüdiger S, Hassan F, Georgiadis ME, Swolana K, Khera A, Mertens A, Franke D, Wohlgemuth K, Dahmer-Heath M, König J, Dafinger C, Liebau MC, Cetiner M, Bergmann C, Soetje B, Haffner D. Primary URECs: a source to better understand the pathology of renal tubular epithelia in pediatric hereditary cystic kidney diseases. Orphanet J Rare Dis 2022; 17:122. [PMID: 35264234 PMCID: PMC8905910 DOI: 10.1186/s13023-022-02265-1] [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: 10/19/2021] [Accepted: 02/20/2022] [Indexed: 11/24/2022] Open
Abstract
Background In pediatric hereditary cystic kidney diseases, epithelial cell defects mostly result from rare, autosomal recessively inherited pathogenic variants in genes encoding proteins of the cilia-centrosome complex. Consequences of individual gene variants on epithelial function are often difficult to predict and can furthermore depend on the patient’s genetic background. Here, we studied urine-derived renal tubular epithelial cells (URECs) from genetically determined, pediatric cohorts of different hereditary cystic kidney diseases, comprising autosomal recessive polycystic kidney disease, nephronophthisis (NPH) and the Bardet Biedl syndrome (BBS). UREC characteristics and behavior in epithelial function-related 3D cell culture were compared in order to identify gene and variant-specific properties and to determine aspects of epithelial (cell) dysfunction. Results UREC preparations from patients (19) and healthy controls (39) were studied in a qualitative and quantitative manner using primary cells cultured for up-to 21 days. In patients with biallelic pathogenic variants in PKHD1 or NPHP genes, we were able to receive satisfactory amounts of URECs of reproducible quality. In BBS patients, UREC yield was lower and more dependent on the individual genotype. In contrast, in UREC preparations derived from healthy controls, no predictable and satisfactory outcome could be established. Considering cell proliferation, tubular origin and epithelial properties in 2D/3D culture conditions, we observed distinct and reproducible epithelial properties of URECs. In particular, the cells from patients carrying PKHD1 variants were characterized by a high incidence of defective morphogenesis of monolayered spheroids—a property proposed to be suitable for corrective intervention. Furthermore, we explored different ways to generate reference cell lines for both—patients and healthy controls—in order to eliminate restrictions in cell number and availability of primary URECs. Conclusions Ex vivo 3D cell culture of primary URECs represents a valuable, non-invasive source to evaluate epithelial cell function in kidney diseases and as such helps to elucidate the functional consequences of rare genetic disorders. In combination with genetically defined control cell lines to be generated in the future, the cultivation of primary URECs could become a relevant tool for testing personalized treatment of epithelial dysfunction in patients with hereditary cystic kidney disease. Supplementary Information The online version contains supplementary material available at 10.1186/s13023-022-02265-1.
Collapse
Affiliation(s)
- Wolfgang H Ziegler
- Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.
| | - Sarah Lüdiger
- Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany
| | - Fatima Hassan
- Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany
| | - Margarita E Georgiadis
- Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany
| | - Kathrin Swolana
- Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany
| | - Amrit Khera
- Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany
| | - Arne Mertens
- Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany
| | - Doris Franke
- Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany
| | - Kai Wohlgemuth
- Department of General Pediatrics, University Children's Hospital Münster, Münster, Germany
| | - Mareike Dahmer-Heath
- Department of General Pediatrics, University Children's Hospital Münster, Münster, Germany
| | - Jens König
- Department of General Pediatrics, University Children's Hospital Münster, Münster, Germany
| | - Claudia Dafinger
- Department of Pediatrics and Center for Molecular Medicine, University Hospital Cologne and Faculty of Medicine, University of Cologne, Cologne, Germany.,Center for Rare Diseases, University Hospital Cologne and Faculty of Medicine, University of Cologne, Cologne, Germany
| | - Max C Liebau
- Department of Pediatrics and Center for Molecular Medicine, University Hospital Cologne and Faculty of Medicine, University of Cologne, Cologne, Germany.,Center for Rare Diseases, University Hospital Cologne and Faculty of Medicine, University of Cologne, Cologne, Germany
| | - Metin Cetiner
- Department of Pediatric Nephrology, Pediatrics II, University of Duisburg-Essen, Essen, Germany
| | - Carsten Bergmann
- Department of Medicine IV, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany.,Medizinische Genetik Mainz, Mainz, Germany
| | - Birga Soetje
- Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.,Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany
| | - Dieter Haffner
- Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany
| |
Collapse
|
|
38
|
Liu M, Cardilla A, Ngeow J, Gong X, Xia Y. Studying Kidney Diseases Using Organoid Models. Front Cell Dev Biol 2022; 10:845401. [PMID: 35309912 PMCID: PMC8927804 DOI: 10.3389/fcell.2022.845401] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Accepted: 02/14/2022] [Indexed: 12/24/2022] Open
Abstract
The prevalence of chronic kidney disease (CKD) is rapidly increasing over the last few decades, owing to the global increase in diabetes, and cardiovascular diseases. Dialysis greatly compromises the life quality of patients, while demand for transplantable kidney cannot be met, underscoring the need to develop novel therapeutic approaches to stop or reverse CKD progression. Our understanding of kidney disease is primarily derived from studies using animal models and cell culture. While cross-species differences made it challenging to fully translate findings from animal models into clinical practice, primary patient cells quickly lose the original phenotypes during in vitro culture. Over the last decade, remarkable achievements have been made for generating 3-dimensional (3D) miniature organs (organoids) by exposing stem cells to culture conditions that mimic the signaling cues required for the development of a particular organ or tissue. 3D kidney organoids have been successfully generated from different types of source cells, including human pluripotent stem cells (hPSCs), adult/fetal renal tissues, and kidney cancer biopsy. Alongside gene editing tools, hPSC-derived kidney organoids are being harnessed to model genetic kidney diseases. In comparison, adult kidney-derived tubuloids and kidney cancer-derived tumoroids are still in their infancy. Herein, we first summarize the currently available kidney organoid models. Next, we discuss recent advances in kidney disease modelling using organoid models. Finally, we consider the major challenges that have hindered the application of kidney organoids in disease modelling and drug evaluation and propose prospective solutions.
Collapse
Affiliation(s)
- Meng Liu
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore
| | - Angelysia Cardilla
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore
| | - Joanne Ngeow
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore
- Cancer Genetics Service, National Cancer Centre Singapore, Singapore, Singapore
| | - Ximing Gong
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore
- *Correspondence: Ximing Gong, ; Yun Xia,
| | - Yun Xia
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore
- *Correspondence: Ximing Gong, ; Yun Xia,
| |
Collapse
|
|
39
|
Yuan Z, Wang S, Tan X, Wang D. New Insights into the Mechanisms of Chaperon-Mediated Autophagy and Implications for Kidney Diseases. Cells 2022; 11:cells11030406. [PMID: 35159216 PMCID: PMC8834181 DOI: 10.3390/cells11030406] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 01/14/2022] [Accepted: 01/18/2022] [Indexed: 02/04/2023] Open
Abstract
Chaperone-mediated autophagy (CMA) is a separate type of lysosomal proteolysis, characterized by its selectivity of substrate proteins and direct translocation into lysosomes. Recent studies have declared the involvement of CMA in a variety of physiologic and pathologic situations involving the kidney, and it has emerged as a potential target for the treatment of kidney diseases. The role of CMA in kidney diseases is context-dependent and appears reciprocally with macroautophagy. Among the renal resident cells, the proximal tubule exhibits a high basal level of CMA activity, and restoration of CMA alleviates the aging-related tubular alternations. The level of CMA is up-regulated under conditions of oxidative stress, such as in acute kidney injury, while it is declined in chronic kidney disease and aging-related kidney diseases, leading to the accumulation of oxidized substrates. Suppressed CMA leads to the kidney hypertrophy in diabetes mellitus, and the increase of CMA contributes to the progress and chemoresistance in renal cell carcinoma. With the progress on the understanding of the cellular functions and uncovering the clinical scenario, the application of targeting CMA in the treatment of kidney diseases is expected.
Collapse
|
|
40
|
Choi D, Gonzalez Z, Ho SY, Bermudez A, Lin NY. Cell-cell adhesion impacts epithelia response to substrate stiffness: Morphology and gene expression. Biophys J 2022; 121:336-346. [PMID: 34864047 PMCID: PMC8790207 DOI: 10.1016/j.bpj.2021.11.2887] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 09/04/2021] [Accepted: 11/29/2021] [Indexed: 01/21/2023] Open
Abstract
Monolayer epithelial cells interact constantly with the substrate they reside on and their surrounding neighbors. As such, the properties of epithelial cells are profoundly governed by the mechanical and molecular cues that arise from both the substrate and contiguous cell neighbors. Although both cell-substrate and cell-cell interactions have been studied individually, these results are difficult to apply to native confluent epithelia, in which both jointly regulate the cell phenotype. Specifically, it remains poorly understood about the intertwined contributions from intercellular adhesion and substrate stiffness on cell morphology and gene expression, two essential microenvironment properties. Here, by adjusting the substrate modulus and altering the intercellular adhesion within confluent kidney epithelia, we found that cell-substrate and cell-cell interactions can mask each other's influence. For example, we found that epithelial cells exhibit an elongated morphological phenotype only when the substrate modulus and intercellular adhesions are both reduced, whereas their motility can be upregulated by either reduction. These results illustrate that combinatorial changes of the physical microenvironment are required to alter cell morphology and gene expression.
Collapse
Affiliation(s)
- David Choi
- Department of Mechanical and Aerospace Engineering, University of California, Los Angeles, California,Corresponding author
| | - Zachary Gonzalez
- Department of Mechanical and Aerospace Engineering, University of California, Los Angeles, California,Department of Physics and Astronomy, University of California, Los Angeles, California
| | - Sum Yat Ho
- Department of Mechanical and Aerospace Engineering, University of California, Los Angeles, California,Department of Chemistry and Biochemistry, University of California, Los Angeles, California
| | - Alexandra Bermudez
- Department of Mechanical and Aerospace Engineering, University of California, Los Angeles, California,Department of Bioengineering, University of California, Los Angeles, California
| | - Neil Y.C. Lin
- Department of Mechanical and Aerospace Engineering, University of California, Los Angeles, California,Department of Bioengineering, University of California, Los Angeles, California,Institute for Quantitative and Computational Biosciences, University of California, Los Angeles
| |
Collapse
|
|
41
|
Klawitter J, Sempio C, Jackson MJ, Smith PH, Hopp K, Chonchol M, Gitomer BY, Christians U, Klawitter J. Endocannabinoid System in Polycystic Kidney Disease. Am J Nephrol 2022; 53:264-272. [PMID: 35263737 PMCID: PMC9173653 DOI: 10.1159/000522113] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 01/06/2022] [Indexed: 12/18/2022]
Abstract
INTRODUCTION Autosomal dominant polycystic kidney disease (ADPKD) is a commonly inherited disorder characterized by renal cyst formation. A major pathological feature of ADPKD is the development of interstitial inflammation. The endocannabinoid (EC) system is present in the kidney and has recently emerged as an important player in inflammation and the pathogenesis of progressive kidney disease. METHODS Data on ECs were collected using a validated mass spectrometry assay from a well-characterized cohort of 102 ADPKD patients (at baseline and after 2- and 4 years on standard vs. rigorous blood-pressure control) and compared to 100 healthy subjects. RESULTS Compared to healthy individuals, we found higher interleukins-6 and -1b as well as reduced plasma levels of anandamide (AEA), 2-arachidonoyl-glycerol (2-AG), and their congeners in ADPKD patients. Baseline AEA concentration negatively associated with the progression of ADPKD as expressed by the yearly percent change in height-corrected total kidney volume and positively with the yearly change in renal function (measured as estimated glomerular filtration rate, ΔeGFR). AEA analog palmitoylethanolamide (PEA) is also associated positively with the yearly change in eGFR. DISCUSSION AND CONCLUSION The results of the present study suggest that ADPKD patients present with lower levels of ECs and that reestablishing the normality of the renal EC system via augmentation of AEA, PEA, and 2-AG levels, either through the increase of their synthesis or through a reduction of their degradation, could be beneficial and may present a promising therapeutic target in said patients.
Collapse
Affiliation(s)
- Jost Klawitter
- Deparment of Anesthesiology, University of Colorado Denver, Denver, Colorado, USA
| | - Cristina Sempio
- Deparment of Anesthesiology, University of Colorado Denver, Denver, Colorado, USA
| | - Matthew J Jackson
- Deparment of Anesthesiology, University of Colorado Denver, Denver, Colorado, USA
| | - Peter H Smith
- Deparment of Anesthesiology, University of Colorado Denver, Denver, Colorado, USA
| | - Katharina Hopp
- Division of Renal Diseases and Hypertension, University of Colorado School of Medicine, Denver, Colorado, USA
| | - Michel Chonchol
- Division of Renal Diseases and Hypertension, University of Colorado School of Medicine, Denver, Colorado, USA
| | - Berenice Y Gitomer
- Division of Renal Diseases and Hypertension, University of Colorado School of Medicine, Denver, Colorado, USA
| | - Uwe Christians
- Deparment of Anesthesiology, University of Colorado Denver, Denver, Colorado, USA
| | - Jelena Klawitter
- Deparment of Anesthesiology, University of Colorado Denver, Denver, Colorado, USA.,Division of Renal Diseases and Hypertension, University of Colorado School of Medicine, Denver, Colorado, USA
| |
Collapse
|
|
42
|
Bowden SA, Rodger EJ, Chatterjee A, Eccles MR, Stayner C. Recent Discoveries in Epigenetic Modifications of Polycystic Kidney Disease. Int J Mol Sci 2021; 22:ijms222413327. [PMID: 34948126 PMCID: PMC8708269 DOI: 10.3390/ijms222413327] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 12/01/2021] [Accepted: 12/07/2021] [Indexed: 01/01/2023] Open
Abstract
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a heritable renal disease that results in end-stage kidney disease, due to the uncontrolled bilateral growth of cysts throughout the kidneys. While it is known that a mutation within a PKD-causing gene is required for the development of ADPKD, the underlying mechanism(s) causing cystogenesis and progression of the disease are not well understood. Limited therapeutic options are currently available to slow the rate of cystic growth. Epigenetic modifications, including DNA methylation, are known to be altered in neoplasia, and several FDA-approved therapeutics target these disease-specific changes. As there are many similarities between ADPKD and neoplasia, we (and others) have postulated that ADPKD kidneys contain alterations to their epigenetic landscape that could be exploited for future therapeutic discovery. Here we summarise the current understanding of epigenetic changes that are associated with ADPKD, with a particular focus on the burgeoning field of ADPKD-specific alterations in DNA methylation.
Collapse
Affiliation(s)
- Sarah A. Bowden
- Department of Pathology, Dunedin School of Medicine, University of Otago, 270 Great King Street, Dunedin 9054, New Zealand; (S.A.B.); (E.J.R.); (A.C.); (M.R.E.)
| | - Euan J. Rodger
- Department of Pathology, Dunedin School of Medicine, University of Otago, 270 Great King Street, Dunedin 9054, New Zealand; (S.A.B.); (E.J.R.); (A.C.); (M.R.E.)
- Maurice Wilkins Centre for Molecular Biodiscovery, Level 2, 3A Symonds Street, Auckland 1010, New Zealand
| | - Aniruddha Chatterjee
- Department of Pathology, Dunedin School of Medicine, University of Otago, 270 Great King Street, Dunedin 9054, New Zealand; (S.A.B.); (E.J.R.); (A.C.); (M.R.E.)
- Maurice Wilkins Centre for Molecular Biodiscovery, Level 2, 3A Symonds Street, Auckland 1010, New Zealand
| | - Michael R. Eccles
- Department of Pathology, Dunedin School of Medicine, University of Otago, 270 Great King Street, Dunedin 9054, New Zealand; (S.A.B.); (E.J.R.); (A.C.); (M.R.E.)
- Maurice Wilkins Centre for Molecular Biodiscovery, Level 2, 3A Symonds Street, Auckland 1010, New Zealand
| | - Cherie Stayner
- Department of Pathology, Dunedin School of Medicine, University of Otago, 270 Great King Street, Dunedin 9054, New Zealand; (S.A.B.); (E.J.R.); (A.C.); (M.R.E.)
- Correspondence: ; Tel.: +64-3-479-5060; Fax: +64-3-479-7136
| |
Collapse
|
|
43
|
Gupta S, Ozimek-Kulik JE, Phillips JK. Nephronophthisis-Pathobiology and Molecular Pathogenesis of a Rare Kidney Genetic Disease. Genes (Basel) 2021; 12:genes12111762. [PMID: 34828368 PMCID: PMC8623546 DOI: 10.3390/genes12111762] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 10/26/2021] [Accepted: 10/27/2021] [Indexed: 12/17/2022] Open
Abstract
The exponential rise in our understanding of the aetiology and pathophysiology of genetic cystic kidney diseases can be attributed to the identification of cystogenic genes over the last three decades. The foundation of this was laid by positional cloning strategies which gradually shifted towards next-generation sequencing (NGS) based screenings. This shift has enabled the discovery of novel cystogenic genes at an accelerated pace unlike ever before and, most notably, the past decade has seen the largest increase in identification of the genes which cause nephronophthisis (NPHP). NPHP is a monogenic autosomal recessive cystic kidney disease caused by mutations in a diverse clade of over 26 identified genes and is the most common genetic cause of renal failure in children. NPHP gene types present with some common pathophysiological features alongside a diverse range of extra-renal phenotypes associated with specific syndromic presentations. This review provides a timely update on our knowledge of this disease, including epidemiology, pathophysiology, anatomical and molecular features. We delve into the diversity of the NPHP causing genes and discuss known molecular mechanisms and biochemical pathways that may have possible points of intersection with polycystic kidney disease (the most studied renal cystic pathology). We delineate the pathologies arising from extra-renal complications and co-morbidities and their impact on quality of life. Finally, we discuss the current diagnostic and therapeutic modalities available for disease management, outlining possible avenues of research to improve the prognosis for NPHP patients.
Collapse
Affiliation(s)
- Shabarni Gupta
- Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW 2109, Australia; (J.E.O.-K.); (J.K.P.)
- Correspondence:
| | - Justyna E. Ozimek-Kulik
- Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW 2109, Australia; (J.E.O.-K.); (J.K.P.)
- School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW 2031, Australia
- Department of Paediatric Nephrology, Sydney Children’s Hospital Network, Children’s Hospital at Westmead, Sydney, NSW 2145, Australia
| | - Jacqueline Kathleen Phillips
- Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW 2109, Australia; (J.E.O.-K.); (J.K.P.)
| |
Collapse
|
|
44
|
|
|
45
|
A human multi-lineage hepatic organoid model for liver fibrosis. Nat Commun 2021; 12:6138. [PMID: 34686668 PMCID: PMC8536785 DOI: 10.1038/s41467-021-26410-9] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 09/28/2021] [Indexed: 12/13/2022] Open
Abstract
To investigate the pathogenesis of a congenital form of hepatic fibrosis, human hepatic organoids were engineered to express the most common causative mutation for Autosomal Recessive Polycystic Kidney Disease (ARPKD). Here we show that these hepatic organoids develop the key features of ARPKD liver pathology (abnormal bile ducts and fibrosis) in only 21 days. The ARPKD mutation increases collagen abundance and thick collagen fiber production in hepatic organoids, which mirrors ARPKD liver tissue pathology. Transcriptomic and other analyses indicate that the ARPKD mutation generates cholangiocytes with increased TGFβ pathway activation, which are actively involved stimulating myofibroblasts to form collagen fibers. There is also an expansion of collagen-producing myofibroblasts with markedly increased PDGFRB protein expression and an activated STAT3 signaling pathway. Moreover, the transcriptome of ARPKD organoid myofibroblasts resemble those present in commonly occurring forms of liver fibrosis. PDGFRB pathway involvement was confirmed by the anti-fibrotic effect observed when ARPKD organoids were treated with PDGFRB inhibitors. Besides providing insight into the pathogenesis of congenital (and possibly acquired) forms of liver fibrosis, ARPKD organoids could also be used to test the anti-fibrotic efficacy of potential anti-fibrotic therapies.
Collapse
|
|
46
|
Zimmerman KA, Song CJ, Aloria EJG, Li Z, Zhou J, Bland SJ, Yashchenko A, Crossman DK, Mrug M, Yoder BK. Early infiltrating macrophage subtype correlates with late-stage phenotypic outcome in a mouse model of hepatorenal fibrocystic disease. J Transl Med 2021; 101:1382-1393. [PMID: 34158590 PMCID: PMC8773463 DOI: 10.1038/s41374-021-00627-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 06/07/2021] [Accepted: 06/07/2021] [Indexed: 11/09/2022] Open
Abstract
Hepatorenal fibrocystic disease (HRFCD) is a genetically inherited disorder related to primary cilia dysfunction in which patients display varying levels of fibrosis, bile duct expansion, and inflammation. In mouse models of HRFCD, the phenotype is greatly impacted by the genetic background in which the mutation is placed. Macrophages are a common factor associated with progression of HRFCD and are also strongly influenced by the genetic background. These data led us to hypothesize that macrophage subtypes that change in relation to the genetic background are responsible for the variable phenotypic outcomes in HRFCD. To test this hypothesis, we utilized a mouse model of HRFCD (Ift88Orpk mice) on the C57BL/6 and BALB/c inbred backgrounds that have well-documented differences in macrophage subtypes. Our analyses of infiltrating macrophage subtypes confirm that genetic strain influences the subtype of infiltrating macrophage present during normal postnatal liver development and in Ift88Orpk livers (Ly6clo in C57BL/6 vs Ly6chi in BALB/c). Each infiltrating macrophage subtype was similarly associated with a unique phenotypic outcome as analysis of liver tissue shows that C57BL/6 Ift88Orpk mice have increased bile duct expansion, but reduced levels of fibrosis compared to BALB/c Ift88Orpk livers. RNA sequencing data suggest that the ability to infiltrate macrophage subtypes to influence the phenotypic outcome may be due to unique ligand-receptor signaling between infiltrating macrophages and cilia dysfunctional biliary epithelium. To evaluate whether specific macrophage subtypes cause the observed phenotypic divergence, we analyzed the liver phenotype in BALB/c Ift88Orpk mice on a CCR2-/- background. Unexpectedly, the loss of Ly6chi macrophages, which were strongly enriched in BALB/c Ift88Orpk mice, did not significantly alter liver fibrosis. These data indicate that macrophage subtypes may correlate with HRFCD phenotypic outcome, but do not directly cause the pathology.
Collapse
Affiliation(s)
- Kurt A Zimmerman
- Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA
- Department of Internal Medicine, Division of Nephrology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Cheng J Song
- Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Ernald J G Aloria
- Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Zhang Li
- Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Juling Zhou
- Department of Medicine, Division of Nephrology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Sarah J Bland
- Department of Internal Medicine, Division of Nephrology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Alex Yashchenko
- Department of Internal Medicine, Division of Nephrology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - David K Crossman
- Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Michal Mrug
- Department of Medicine, Division of Nephrology, University of Alabama at Birmingham, Birmingham, AL, USA
- Department of Veterans Affairs Medical Center, 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.
| |
Collapse
|
|
47
|
Lu L, Liu Q, Zhi L, Che X, Xiao B, Cui M, Yu M, Yang B, Zhang J, Zhang B. Establishment of a Ciliogenesis-Associated Signaling Model for Polycystic Kidney Disease. Kidney Blood Press Res 2021; 46:693-701. [PMID: 34469896 DOI: 10.1159/000517408] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 05/21/2021] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Polycystic kidney disease (PKD) represents the most prevalent inherited progressive kidney disorder in humans. Due to complexity of the genetic network behind the disease, the molecular mechanisms of PKD are still poorly understood yet. OBJECTIVES This study aimed to develop a ciliogenesis-associated gene network for PKD patients and comprehensively understand the molecular mechanisms underlying the disease. METHOD The potential hub genes were selected based on the differential expression analysis from the GEO database. Meanwhile, the primary hub genes were further elucidated by both in vivo and in vitro experiments. RESULTS In this study, we established a comprehensive differentially expressed genes profile (including GNAS, PI4KB, UMOD, SLC7A13, and MIOX) for PKD patients compared with the control specimen. At the same time, enrichment analysis was utilized to demonstrate that the G-protein-related signaling and cilia assembling signaling pathways were closely associated with PKD development. The further investigations of the interaction between 2 genes (GNAS and PI4KB) with in vivo and in vitro analyses revealed that PI4KB functioned as a downstream factor for GNAS and spontaneously activated the phosphorylation of Akt into p-Akt for ciliogenesis in PKD formation. The PI4KB depletion mutant zebrafish model displayed a PKD phenotype as well as absence of primary cilia in the kidney. CONCLUSIONS Collectively, our work discovered an innovative potential signaling pathway model for PKD formation, which provided a valuable insight for future study of the mechanism of this disease.
Collapse
Affiliation(s)
- Ling Lu
- Department of Nephrology, Tianjin First Central Hospital, Tianjin, China
| | - Qiuling Liu
- Affiliated Hospital of Guangdong Medical University & Key Laboratory of Zebrafish Model for Development and Disease of Guangdong Medical University, Zhanjiang, China
| | - Lei Zhi
- Department of Immunology, Tianjin Key Laboratory of Cellular and Molecular Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Xuchun Che
- Department of Immunology, Tianjin Key Laboratory of Cellular and Molecular Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Bo Xiao
- Department of Immunology, Tianjin Key Laboratory of Cellular and Molecular Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Mingxuan Cui
- School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Mingyu Yu
- Department of Immunology, Tianjin Key Laboratory of Cellular and Molecular Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Bing Yang
- Department of Cell Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Jingjing Zhang
- Affiliated Hospital of Guangdong Medical University & Key Laboratory of Zebrafish Model for Development and Disease of Guangdong Medical University, Zhanjiang, China
| | - Bo Zhang
- Department of Immunology, Tianjin Key Laboratory of Cellular and Molecular Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| |
Collapse
|
|
48
|
He J, Zhang S, Qiu Z, Li X, Huang H, Jin W, Xu Y, Shao G, Wang L, Meng J, Wang S, Geng X, Jia Y, Li M, Yang B, Jenny Lu HA, Zhou H. Inhibiting Focal Adhesion Kinase Ameliorates Cyst Development in Polycystin-1-Deficient Polycystic Kidney Disease in Animal Model. J Am Soc Nephrol 2021; 32:2159-2174. [PMID: 34465607 PMCID: PMC8729842 DOI: 10.1681/asn.2020111560] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 04/07/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Autosomal dominant polycystic kidney disease (ADPKD) is characterized by numerous cysts originating from renal tubules and is associated with significant tubular epithelial cell proliferation. Focal adhesion kinase (FAK) promotes tumor growth by regulating multiple proliferative pathways. METHODS We established the forskolin (FSK)-induced three-dimensional (3D) Madin-Darby Canine Kidney cystogenesis model and 8-bromoadenosine-3`,5`-cyclic monophosphate-stimulated cyst formation in ex vivo embryonic kidney culture. Cultured human renal cyst-lining cells (OX-161) and normal tubular epithelial cells were treated with FAK inhibitors or transfected with green fluorescent protein-tagged FAK mutant plasmids for proliferation study. Furthermore, we examined the role of FAK in two transgenic ADPKD animal models, the kidney-specific Pkd1 knockout and the collecting duct-specific Pkd1 knockout mouse models. RESULTS FAK activity was significantly elevated in OX-161 cells and in two ADPKD mouse models. Inhibiting FAK activity reduced cell proliferation in OX-161 cells and prevented cyst growth in ex vivo and 3D cyst models. In tissue-specific Pkd1 knockout mouse models, FAK inhibitors retarded cyst development and mitigated renal function decline. Mechanically, FSK stimulated FAK activation in tubular epithelial cells, which was blocked by a protein kinase A (PKA) inhibitor. Inhibition of FAK activation by inhibitors or transfected cells with mutant FAK constructs interrupted FSK-mediated Src activation and upregulation of ERK and mTOR pathways. CONCLUSIONS Our study demonstrates the critical involvement of FAK in renal cyst development, suggests that FAK is a potential therapeutic target in treating patients with ADPKD, and highlights the role of FAK in cAMP-PKA-regulated proliferation.
Collapse
Affiliation(s)
- Jinzhao He
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China,Center for Systems Biology, Program in Membrane Biology and Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
| | - Shun Zhang
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Zhiwei Qiu
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Xiaowei Li
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Huihui Huang
- Center for Systems Biology, Program in Membrane Biology and Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts,Harvard Medical School, Boston, Massachusetts
| | - William Jin
- Division of Graduate Medical Sciences, Boston University School of Medicine, Boston, Massachusetts
| | - Yue Xu
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Guangying Shao
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Liang Wang
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Jia Meng
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Shuyuan Wang
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Xiaoqiang Geng
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Yingli Jia
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Min Li
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China,Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, China
| | - Baoxue Yang
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China,Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, China
| | - Hua A. Jenny Lu
- Center for Systems Biology, Program in Membrane Biology and Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts,Harvard Medical School, Boston, Massachusetts
| | - Hong Zhou
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China,Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, China
| |
Collapse
|
|
49
|
Gopalan J, Omar MH, Roy A, Cruz NM, Falcone J, Jones KN, Forbush KA, Himmelfarb J, Freedman BS, Scott JD. Targeting an anchored phosphatase-deacetylase unit restores renal ciliary homeostasis. eLife 2021; 10:e67828. [PMID: 34250905 PMCID: PMC8291974 DOI: 10.7554/elife.67828] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 07/11/2021] [Indexed: 11/13/2022] Open
Abstract
Pathophysiological defects in water homeostasis can lead to renal failure. Likewise, common genetic disorders associated with abnormal cytoskeletal dynamics in the kidney collecting ducts and perturbed calcium and cAMP signaling in the ciliary compartment contribute to chronic kidney failure. We show that collecting ducts in mice lacking the A-Kinase anchoring protein AKAP220 exhibit enhanced development of primary cilia. Mechanistic studies reveal that AKAP220-associated protein phosphatase 1 (PP1) mediates this phenotype by promoting changes in the stability of histone deacetylase 6 (HDAC6) with concomitant defects in actin dynamics. This proceeds through a previously unrecognized adaptor function for PP1 as all ciliogenesis and cytoskeletal phenotypes are recapitulated in mIMCD3 knock-in cells expressing a phosphatase-targeting defective AKAP220-ΔPP1 mutant. Pharmacological blocking of local HDAC6 activity alters cilia development and reduces cystogenesis in kidney-on-chip and organoid models. These findings identify the AKAP220-PPI-HDAC6 pathway as a key effector in primary cilia development.
Collapse
Affiliation(s)
- Janani Gopalan
- Department of Pharmacology, University of WashingtonSeattleUnited States
| | - Mitchell H Omar
- Department of Pharmacology, University of WashingtonSeattleUnited States
| | - Ankita Roy
- Kidney Research Institute, Division of Nephrology, Department of Laboratory Medicine and Pathology, University of WashingtonSeattleUnited States
- Institute for Stem Cell and Regenerative Medicine, University of WashingtonSeattleUnited States
| | - Nelly M Cruz
- Kidney Research Institute, Division of Nephrology, Department of Laboratory Medicine and Pathology, University of WashingtonSeattleUnited States
- Institute for Stem Cell and Regenerative Medicine, University of WashingtonSeattleUnited States
| | - Jerome Falcone
- Department of Pharmacology, University of WashingtonSeattleUnited States
| | - Kiana N Jones
- Department of Pharmacology, University of WashingtonSeattleUnited States
| | | | - Jonathan Himmelfarb
- Kidney Research Institute, Division of Nephrology, Department of Laboratory Medicine and Pathology, University of WashingtonSeattleUnited States
| | - Benjamin S Freedman
- Kidney Research Institute, Division of Nephrology, Department of Laboratory Medicine and Pathology, University of WashingtonSeattleUnited States
- Institute for Stem Cell and Regenerative Medicine, University of WashingtonSeattleUnited States
| | - John D Scott
- Department of Pharmacology, University of WashingtonSeattleUnited States
| |
Collapse
|
|
50
|
Collini A, Benigni R, Ruggieri G, Carmellini PM. Laparoscopic Nephrectomy for Massive Kidneys in Polycystic Kidney Disease. JSLS 2021; 25:JSLS.2020.00107. [PMID: 33879988 PMCID: PMC8035816 DOI: 10.4293/jsls.2020.00107] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
Background and Objectives: Laparoscopic nephrectomy is now considered a feasible surgical approach, even for large kidneys. In the case of massive kidneys, laparoscopy can be problematic, so that some authors suggest an open approach. However, previous studies have shown that hand-assisted laparoscopic nephrectomy (HALN) may represent a useful compromise. We describe our hand-assisted laparoscopic technique for nephrectomy of large kidneys (> 2500 g) to encourage the use of laparoscopy for nephrectomy in autosomal dominant polycystic kidney disease. Methods: We retrospectively analyzed data from 26 nephrectomies in 17 patients who underwent HALN for ADPKD and compared them to a group of 22 nephrectomies in 18 patients with open surgical technique. Results: The duration of the procedure was significantly longer in the laparoscopic group, with a median of 180 minutes versus 90 minutes for the unilateral nephrectomies, and 240 minutes versus 122 minutes for the bilateral procedures. The median kidney weight in the open group was 2500 g (range 1300 – 4500 g), while the median weight in the HALN group was 2375 g (range 1000 – 4700 g). The median hospital stay was comparable. No significant differences were recorded in the intra- and postoperative complication rate. Conclusion: Hand-assisted laparoscopic nephrectomy can be considered a technique of choice for patients suffering from ADPKD requiring nephrectomy, also with massive kidneys weighing more than 3500 g. Compared to open nephrectomy, HALN can be performed safely, with reasonably longer operating times and without major complications, and offers a significant reduction in hospitalization time, pain and postoperative discomfort.
Collapse
Affiliation(s)
- Andrea Collini
- UO Chirurgia Trapianti Renali, Azienda Ospedaliero-Universitaria Senese, Viale Bracci 14, 53100 Siena, Italy
| | - Roberto Benigni
- UO Chirurgia Trapianti Renali, Azienda Ospedaliero-Universitaria Senese, Viale Bracci 14, 53100 Siena, Italy
| | - Giuliana Ruggieri
- UO Chirurgia Trapianti Renali, Azienda Ospedaliero-Universitaria Senese, Viale Bracci 14, 53100 Siena, Italy
| | - Prof Mario Carmellini
- UO Chirurgia Trapianti Renali, Azienda Ospedaliero-Universitaria Senese, Viale Bracci 14, 53100 Siena, Italy
| |
Collapse
|