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Article ; Online: ARF6, a component of intercellular bridges, is essential for spermatogenesis in mice.

Wong, Hetty N / Chen, Tingfang / Wang, P Jeremy / Holzman, Lawrence B

2024 Volume 508, Page(s) 46–63

Abstract: Male germ cells are connected by intercellular bridges (ICBs) in a syncytium due to incomplete cytokinesis. Syncytium is thought to be important for synchronized germ cell development by interchange of cytoplasmic factors via ICBs. Mammalian ADP- ... ...

Abstract	Male germ cells are connected by intercellular bridges (ICBs) in a syncytium due to incomplete cytokinesis. Syncytium is thought to be important for synchronized germ cell development by interchange of cytoplasmic factors via ICBs. Mammalian ADP-ribosylation factor 6 (ARF6) is a small GTPase that is involved in many cellular mechanisms including but not limited to regulating cellular structure, motility, vesicle trafficking and cytokinesis. ARF6 localizes to ICBs in spermatogonia and spermatocytes in mice. Here we report that mice with global depletion of ARF6 in adulthood using Ubc-CreERT2 display no observable phenotypes but are male sterile. ARF6-deficient males display a progressive loss of germ cells, including LIN28A-expressing spermatogonia, and ultimately develop Sertoli-cell-only syndrome. Specifically, intercellular bridges are lost in ARF6-deficient testis. Furthermore, germ cell-specific inactivation using the Ddx4-CreERT2 results in the same testicular morphological phenotype, showing the germ cell-intrinsic requirement of ARF6. Therefore, ARF6 is essential for spermatogenesis in mice and this function is conserved from Drosophila to mammals.
MeSH term(s)	Animals ; Female ; Male ; Mice ; ADP-Ribosylation Factor 6 ; Drosophila ; Mammals ; Spermatocytes ; Spermatogenesis/genetics ; Spermatogonia ; Testis
Chemical Substances	ADP-Ribosylation Factor 6 ; Atf6 protein, mouse
Language	English
Publishing date	2024-01-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	1114-9
ISSN	1095-564X ; 0012-1606
ISSN (online)	1095-564X
ISSN	0012-1606
DOI	10.1016/j.ydbio.2024.01.007
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Article ; Online: The 14th International Podocyte Conference 2023: from podocyte biology to glomerular medicine.

Koehler, Sybille / Hengel, Felicitas E / Dumoulin, Bernhard / Damashek, Laurel / Holzman, Lawrence B / Susztak, Katalin / Huber, Tobias B

Kidney international

2024 Volume 105, Issue 5, Page(s) 935–952

Abstract: The 14th International Podocyte Conference took place in Philadelphia, Pennsylvania, USA from May 23 to 26, 2023. It commenced with an early-career researchers' meeting on May 23, providing young scientists with a platform to present and discuss their ... ...

Abstract	The 14th International Podocyte Conference took place in Philadelphia, Pennsylvania, USA from May 23 to 26, 2023. It commenced with an early-career researchers' meeting on May 23, providing young scientists with a platform to present and discuss their research findings. Throughout the main conference, 29 speakers across 9 sessions shared their insights on podocyte biology, glomerular medicine, novel technologic advancements, and translational approaches. Additionally, the event featured 3 keynote lectures addressing engineered chimeric antigen receptor T cell- and mRNA-based therapies and the use of biobanks for enhanced disease comprehension. Furthermore, 4 brief oral abstract sessions allowed scientists to present their findings to a broad audience. The program also included a panel discussion addressing the challenges of conducting human research within the American Black community. Remarkably, after a 5-year hiatus from in-person conferences, the 14th International Podocyte Conference successfully convened scientists from around the globe, fostering the presentation and discussion of crucial research findings, as summarized in this review. Furthermore, to ensure continuous and sustainable education, research, translation, and trial medicine related to podocyte and glomerular diseases for the benefit of patients, the International Society of Glomerular Disease was officially launched during the conference.
MeSH term(s)	Humans ; Podocytes ; Kidney Glomerulus ; Kidney Diseases/therapy ; Biology
Language	English
Publishing date	2024-03-04
Publishing country	United States
Document type	Review ; Journal Article
ZDB-ID	120573-0
ISSN	1523-1755 ; 0085-2538
ISSN (online)	1523-1755
ISSN	0085-2538
DOI	10.1016/j.kint.2024.01.042
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Zs.A 797: Show issues

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Article ; Online: Clinical Relevance of Computationally Derived Attributes of Peritubular Capillaries from Kidney Biopsies.

Chen, Yijiang / Zee, Jarcy / Janowczyk, Andrew R / Rubin, Jeremy / Toro, Paula / Lafata, Kyle J / Mariani, Laura H / Holzman, Lawrence B / Hodgin, Jeffrey B / Madabhushi, Anant / Barisoni, Laura

Kidney360

2023 Volume 4, Issue 5, Page(s) 648–658

MeSH term(s)	Capillaries/pathology ; Clinical Relevance ; Kidney/pathology ; Kidney Transplantation ; Biopsy
Language	English
Publishing date	2023-04-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ISSN	2641-7650
ISSN (online)	2641-7650
DOI	10.34067/KID.0000000000000116
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Article ; Online: Rationale and design of the Nephrotic Syndrome Study Network (NEPTUNE) Match in glomerular diseases: designing the right trial for the right patient, today.

Trachtman, Howard / Desmond, Hailey / Williams, Amanda L / Mariani, Laura H / Eddy, Sean / Ju, Wenjun / Barisoni, Laura / Ascani, Heather K / Uhlmann, Wendy R / Spino, Cathie / Holzman, Lawrence B / Sedor, John R / Gadegbeku, Crystal / Subramanian, Lalita / Lienczewski, Chrysta C / Manieri, Tina / Roberts, Scott J / Gipson, Debbie S / Kretzler, Matthias

Kidney international

2024 Volume 105, Issue 2, Page(s) 218–230

Abstract: Glomerular diseases are classified using a descriptive taxonomy that is not reflective of the heterogeneous underlying molecular drivers. This limits not only diagnostic and therapeutic patient management, but also impacts clinical trials evaluating ... ...

Abstract	Glomerular diseases are classified using a descriptive taxonomy that is not reflective of the heterogeneous underlying molecular drivers. This limits not only diagnostic and therapeutic patient management, but also impacts clinical trials evaluating targeted interventions. The Nephrotic Syndrome Study Network (NEPTUNE) is poised to address these challenges. The study has enrolled >850 pediatric and adult patients with proteinuric glomerular diseases who have contributed to deep clinical, histologic, genetic, and molecular profiles linked to long-term outcomes. The NEPTUNE Knowledge Network, comprising combined, multiscalar data sets, captures each participant's molecular disease processes at the time of kidney biopsy. In this editorial, we describe the design and implementation of NEPTUNE Match, which bridges a basic science discovery pipeline with targeted clinical trials. Noninvasive biomarkers have been developed for real-time pathway analyses. A Molecular Nephrology Board reviews the pathway maps together with clinical, laboratory, and histopathologic data assembled for each patient to compile a Match report that estimates the fit between the specific molecular disease pathway(s) identified in an individual patient and proposed clinical trials. The NEPTUNE Match report is communicated using established protocols to the patient and the attending nephrologist for use in their selection of available clinical trials. NEPTUNE Match represents the first application of precision medicine in nephrology with the aim of developing targeted therapies and providing the right medication for each patient with primary glomerular disease.
MeSH term(s)	Adult ; Child ; Humans ; Biomarkers ; Clinical Trials as Topic ; Kidney Diseases ; Kidney Glomerulus/pathology ; Nephrotic Syndrome/diagnosis ; Nephrotic Syndrome/genetics ; Nephrotic Syndrome/therapy
Chemical Substances	Biomarkers
Language	English
Publishing date	2024-01-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	120573-0
ISSN	1523-1755 ; 0085-2538
ISSN (online)	1523-1755
ISSN	0085-2538
DOI	10.1016/j.kint.2023.11.018
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Article ; Online: Kidney Biopsy Features Most Predictive of Clinical Outcomes in the Spectrum of Minimal Change Disease and Focal Segmental Glomerulosclerosis.

Zee, Jarcy / Liu, Qian / Smith, Abigail R / Hodgin, Jeffrey B / Rosenberg, Avi / Gillespie, Brenda W / Holzman, Lawrence B / Barisoni, Laura / Mariani, Laura H

Journal of the American Society of Nephrology : JASN

2022 Volume 33, Issue 7, Page(s) 1411–1426

Abstract: Background: Heterogeneity in disease course and treatment response among patients with MCD/FSGS necessitates a granular evaluation of kidney tissue features. This study aimed to identify histologic and ultrastructural descriptors of structural changes ... ...

Abstract	Background: Heterogeneity in disease course and treatment response among patients with MCD/FSGS necessitates a granular evaluation of kidney tissue features. This study aimed to identify histologic and ultrastructural descriptors of structural changes most predictive of clinical outcomes in the Nephrotic Syndrome Study Network (NEPTUNE). Methods: Forty-eight histologic (37 glomerular, 9 tubulointerstitial, 2 vascular) and 20 ultrastructural descriptors were quantified by applying the NEPTUNE Digital Pathology Scoring System to NEPTUNE kidney biopsies. Outcomes included time from biopsy to disease progression, first complete remission of proteinuria, and treatment response. Relative importance of pathology and clinical predictors was obtained from random forest models, and predictive discrimination was assessed. Results: Among 224 participants (34% Black, 24% Hispanic), model performance was excellent, with predictive discrimination of 0.9 for disease progression, 0.85 for complete remission, and 0.81 for treatment response. The most predictive descriptors of outcomes included both conventional- Conclusions: The most predictive descriptors of clinical outcomes among MCD/FSGS patients reflected structural changes in multiple renal compartments. Reporting these descriptors should be standardized to guide prognostication of proteinuric glomerular diseases.
MeSH term(s)	Biopsy ; Disease Progression ; Fibrosis ; Glomerulosclerosis, Focal Segmental/pathology ; Humans ; Kidney/pathology ; Kidney Diseases/pathology ; Nephrosis, Lipoid/pathology ; Nephrotic Syndrome/pathology ; Prognosis ; Sclerosis
Language	English
Publishing date	2022-05-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1085942-1
ISSN	1533-3450 ; 1046-6673
ISSN (online)	1533-3450
ISSN	1046-6673
DOI	10.1681/ASN.2021101396
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Article ; Online: Association of COVID-19 Versus COVID-19 Vaccination With Kidney Function and Disease Activity in Primary Glomerular Disease: A Report of the Cure Glomerulonephropathy Study.

Wang, Chia-Shi / Glenn, Dorey A / Helmuth, Margaret / Smith, Abigail R / Bomback, Andrew S / Canetta, Pietro A / Coppock, Gaia M / Khalid, Myda / Tuttle, Katherine R / Bou-Matar, Raed / Greenbaum, Larry A / Robinson, Bruce M / Holzman, Lawrence B / Smoyer, William E / Rheault, Michelle N / Gipson, Debbie / Mariani, Laura H

American journal of kidney diseases : the official journal of the National Kidney Foundation

2023 Volume 83, Issue 1, Page(s) 37–46

Abstract: Rationale & objective: Patients with glomerular disease (GN) may be at increased risk of severe COVID-19, yet concerns over vaccines causing disease relapse may lead to vaccine hesitancy. We examined the associations of COVID-19 with longitudinal kidney ...

Abstract	Rationale & objective: Patients with glomerular disease (GN) may be at increased risk of severe COVID-19, yet concerns over vaccines causing disease relapse may lead to vaccine hesitancy. We examined the associations of COVID-19 with longitudinal kidney function and proteinuria and compared these with similar associations with COVID-19 vaccination. Study design: Observational cohort study from July 1, 2021, to January 1, 2023. Setting & participants: A prospective observational study network of 71 centers from North America and Europe (CureGN) with children and adults with primary minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy. Exposure: COVID-19 and COVID-19 vaccination. Outcome: Repeated measure of estimated glomerular filtration rate (eGFR); recurrent time-to-event outcome of GN disease worsening as defined by doubling of the urinary protein-creatinine ratio (UPCR) to at least 1.5g/g or increase in dipstick urine protein by 2 ordinal levels to 3+(300mg/dL) or above. Analytical approach: Interrupted time series analysis for eGFR. Prognostic matched sequential stratification recurrent event analysis for GN disease worsening. Results: Among 2,055 participants, 722 (35%) reported COVID-19 infection; of these, 92 (13%) were hospitalized, and 3 died (<1%). The eGFR slope before COVID-19 infection was-1.40mL/min/1.73m Limitations: Infrequent or short follow-up. Conclusions: Among patients with primary GN, COVID-19 infection was severe for 1 in 8 cases and was associated with subsequent worsening of GN disease activity, as defined by proteinuria. By contrast, vaccination against COVID-19 was not associated with change in disease activity or kidney function decline. These results support COVID-19 vaccination for patients with GN. Plain-language summary: In this cohort study of 2,055 patients with minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy, COVID-19 resulted in hospitalization or death for 1 in 8 cases and was associated with a 35% increase in risk for worsening proteinuria. By contrast, vaccination did not appear to adversely affect kidney function or proteinuria. Our data support vaccination for COVID-19 in patients with glomerular disease.
MeSH term(s)	Adult ; Child ; Humans ; Cohort Studies ; COVID-19/complications ; COVID-19/epidemiology ; COVID-19 Vaccines/adverse effects ; Glomerular Filtration Rate ; Glomerulonephritis, IGA/urine ; Glomerulonephritis, Membranous ; Glomerulosclerosis, Focal Segmental ; Kidney Glomerulus ; Nephrosis, Lipoid ; Proteinuria/epidemiology ; Vaccination ; Prospective Studies
Chemical Substances	COVID-19 Vaccines
Language	English
Publishing date	2023-08-31
Publishing country	United States
Document type	Observational Study ; Journal Article
ZDB-ID	604539-x
ISSN	1523-6838 ; 0272-6386
ISSN (online)	1523-6838
ISSN	0272-6386
DOI	10.1053/j.ajkd.2023.07.008
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Zs.A 1669: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Signaling from the podocyte intercellular junction to the actin cytoskeleton.

George, Britta / Holzman, Lawrence B

Seminars in nephrology

2012 Volume 32, Issue 4, Page(s) 307–318

Abstract: Observations of hereditary glomerular disease support the contention that podocyte intercellular junction proteins are essential for junction formation and maintenance. Genetic deletion of most of these podocyte intercellular junction proteins results in ...

Abstract	Observations of hereditary glomerular disease support the contention that podocyte intercellular junction proteins are essential for junction formation and maintenance. Genetic deletion of most of these podocyte intercellular junction proteins results in foot process effacement and proteinuria. This review focuses on the current understanding of molecular mechanisms by which podocyte intercellular junction proteins such as the nephrin-neph1-podocin-receptor complex coordinate cytoskeletal dynamics and thus intercellular junction formation, maintenance, and injury-dependent remodeling.
MeSH term(s)	Actin Cytoskeleton/metabolism ; Animals ; Humans ; Intercellular Junctions/metabolism ; Intercellular Junctions/pathology ; Intracellular Signaling Peptides and Proteins/metabolism ; Membrane Proteins/metabolism ; Podocytes/cytology ; Podocytes/metabolism ; Signal Transduction
Chemical Substances	Intracellular Signaling Peptides and Proteins ; KIRREL1 protein, human ; Membrane Proteins ; NPHS2 protein ; nephrin
Language	English
Publishing date	2012-01-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	604652-6
ISSN	1558-4488 ; 0270-9295
ISSN (online)	1558-4488
ISSN	0270-9295
DOI	10.1016/j.semnephrol.2012.06.002
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Article ; Online: Podocytes: gaining a foothold.

Garg, Puneet / Holzman, Lawrence B

Experimental cell research

2012 Volume 318, Issue 9, Page(s) 955–963

Abstract: In an attempt to understand the basis of glomerular disease, significant progress has been made in understanding the mechanisms that determine podocyte development and the maintenance of podocyte health. This review examines recent advances in this area ... ...

Abstract	In an attempt to understand the basis of glomerular disease, significant progress has been made in understanding the mechanisms that determine podocyte development and the maintenance of podocyte health. This review examines recent advances in this area focusing on the podocyte intercellular junction, actin cytoskeletal dynamics, and determinants of podocyte cell polarity, autophagy and mTOR biology.
MeSH term(s)	Animals ; Cell Polarity ; Humans ; Intercellular Junctions/metabolism ; Kidney Diseases/metabolism ; Kidney Glomerulus/metabolism ; Membrane Proteins/metabolism ; Podocytes/metabolism
Chemical Substances	Membrane Proteins
Language	English
Publishing date	2012-03-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	1493-x
ISSN	1090-2422 ; 0014-4827
ISSN (online)	1090-2422
ISSN	0014-4827
DOI	10.1016/j.yexcr.2012.02.030
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Article ; Online: Initial insight on the determinants of podocyte polarity.

Holzman, Lawrence B / Garg, Puneet

Journal of the American Society of Nephrology : JASN

2009 Volume 20, Issue 4, Page(s) 683–685

MeSH term(s)	Adaptor Proteins, Signal Transducing ; Animals ; Cell Cycle Proteins/physiology ; Cell Movement ; Cell Polarity/physiology ; Humans ; Intercellular Junctions/physiology ; Kidney Diseases/physiopathology ; Kidney Glomerulus/physiopathology ; Membrane Proteins/genetics ; Membrane Proteins/physiology ; Podocytes/physiology ; Reference Values
Chemical Substances	Adaptor Proteins, Signal Transducing ; Cell Cycle Proteins ; Membrane Proteins ; PARD3 protein, human ; nephrin
Language	English
Publishing date	2009-03-25
Publishing country	United States
Document type	Editorial ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Comment
ZDB-ID	1085942-1
ISSN	1533-3450 ; 1046-6673
ISSN (online)	1533-3450
ISSN	1046-6673
DOI	10.1681/ASN.2009020217
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Article ; Online: Quantification of Glomerular Structural Lesions: Associations With Clinical Outcomes and Transcriptomic Profiles in Nephrotic Syndrome.

Hodgin, Jeffrey B / Mariani, Laura H / Zee, Jarcy / Liu, Qian / Smith, Abigail R / Eddy, Sean / Hartman, John / Hamidi, Habib / Gaut, Joseph P / Palmer, Matthew B / Nast, Cynthia C / Chang, Anthony / Hewitt, Stephen / Gillespie, Brenda W / Kretzler, Matthias / Holzman, Lawrence B / Barisoni, Laura

American journal of kidney diseases : the official journal of the National Kidney Foundation

2021 Volume 79, Issue 6, Page(s) 807–819.e1

Abstract: Rationale & objective: The current classification system for focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) does not fully capture the complex structural changes in kidney biopsies nor the clinical and molecular heterogeneity ...

Abstract	Rationale & objective: The current classification system for focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) does not fully capture the complex structural changes in kidney biopsies nor the clinical and molecular heterogeneity of these diseases. Study design: Prospective observational cohort study. Setting & participants: 221 MCD and FSGS patients enrolled in the Nephrotic Syndrome Study Network (NEPTUNE). Exposure: The NEPTUNE Digital Pathology Scoring System (NDPSS) was applied to generate scores for 37 glomerular descriptors. Outcome: Time from biopsy to complete proteinuria remission, time from biopsy to kidney disease progression (40% estimated glomerular filtration rate [eGFR] decline or kidney failure), and eGFR over time. Analytical approach: Cluster analysis was used to group patients with similar morphologic characteristics. Glomerular descriptors and patient clusters were assessed for associations with outcomes using adjusted Cox models and linear mixed models. Messenger RNA from glomerular tissue was used to assess differentially expressed genes between clusters and identify genes associated with individual descriptors driving cluster membership. Results: Three clusters were identified: X (n = 56), Y (n = 68), and Z (n = 97). Clusters Y and Z had higher probabilities of proteinuria remission (HRs of 1.95 [95% CI, 0.99-3.85] and 3.29 [95% CI, 1.52-7.13], respectively), lower hazards of disease progression (HRs of 0.22 [95% CI, 0.08-0.57] and 0.11 [95% CI, 0.03-0.45], respectively), and lower loss of eGFR over time compared with X. Cluster X had 1,920 genes that were differentially expressed compared with Y+Z; these reflected activation of pathways of immune response and inflammation. Six descriptors driving the clusters individually correlated with clinical outcomes and gene expression. Limitations: Low prevalence of some descriptors and biopsy at a single time point. Conclusions: The NDPSS allows for categorization of FSGS/MCD patients into clinically and biologically relevant subgroups, and uncovers histologic parameters associated with clinical outcomes and molecular signatures not included in current classification systems.
MeSH term(s)	Disease Progression ; Glomerulosclerosis, Focal Segmental/pathology ; Humans ; Kidney Diseases/complications ; Nephrosis, Lipoid/pathology ; Nephrotic Syndrome/pathology ; Prognosis ; Prospective Studies ; Proteinuria/pathology ; Transcriptome
Language	English
Publishing date	2021-12-03
Publishing country	United States
Document type	Journal Article ; Observational Study ; Research Support, N.I.H., Extramural
ZDB-ID	604539-x
ISSN	1523-6838 ; 0272-6386
ISSN (online)	1523-6838
ISSN	0272-6386
DOI	10.1053/j.ajkd.2021.10.004
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