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Article ; Online: WIP1 inhibition as a new therapeutic strategy for collapsing glomerulopathy.

Akilesh, Shreeram

2024 Volume 105, Issue 5, Page(s) 923–924

Abstract: Collapsing glomerulopathy (CG) is an aggressive variant of focal and segmental glomerulosclerosis. Understanding the diverse mechanisms that can drive CG promises to uncover new therapeutic strategies. In this issue, Duret et al. identify WIP1 ... ...

Abstract	Collapsing glomerulopathy (CG) is an aggressive variant of focal and segmental glomerulosclerosis. Understanding the diverse mechanisms that can drive CG promises to uncover new therapeutic strategies. In this issue, Duret et al. identify WIP1 phosphatase as a therapeutic target for CG. Using genetic ablation and pharmacologic inhibition, they show that blockade of WIP1 activity is protective in 2 different mouse models of CG. This study highlights the complex interplay of glomerular signaling pathways in CG and offers hope for targeted therapies.
MeSH term(s)	Mice ; Animals ; Glomerulosclerosis, Focal Segmental/drug therapy ; Kidney Glomerulus ; Kidney Diseases/drug therapy
Language	English
Publishing date	2024-02-22
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.2024.02.011
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Article ; Online: Collapsing glomerulopathy: unraveling varied pathogeneses.

Smith, Kelly D / Akilesh, Shreeram

Current opinion in nephrology and hypertension

2023 Volume 32, Issue 3, Page(s) 213–222

Abstract: Purpose of review: Collapsing glomerulopathy presents clinically with nephrotic syndrome and rapid progressive loss of kidney function. Animal models and patient studies have uncovered numerous clinical and genetic conditions associated with collapsing ... ...

Abstract	Purpose of review: Collapsing glomerulopathy presents clinically with nephrotic syndrome and rapid progressive loss of kidney function. Animal models and patient studies have uncovered numerous clinical and genetic conditions associated with collapsing glomerulopathy, as well as putative mechanisms, which will be reviewed here. Recent findings: Collapsing glomerulopathy is classified pathologically as a variant of focal and segmental glomerulosclerosis (FSGS). As such, most research efforts have focused on the causative role of podocyte injury in driving the disease. However, studies have also shown that injury to the glomerular endothelium or interruption of the podocyte-glomerular endothelial cell signaling axis can also cause collapsing glomerulopathy. Furthermore, emerging technologies are now enabling exploration of diverse molecular pathways that can precipitate collapsing glomerulopathy using biopsies from patients with the disease. Summary: Since its original description in the 1980s, collapsing glomerulopathy has been the subject of intense study, and these efforts have uncovered numerous insights into potential disease mechanisms. Newer technologies will enable profiling of the intra-patient and inter-patient variability in collapsing glomerulopathy mechanisms directly in patient biopsies, which will improve the diagnosis and classification of collapsing glomerulopathy.
MeSH term(s)	Animals ; Humans ; Kidney Diseases/pathology ; Glomerulosclerosis, Focal Segmental/genetics ; Kidney Glomerulus/pathology ; Nephrotic Syndrome/genetics ; Podocytes/pathology
Language	English
Publishing date	2023-02-09
Publishing country	England
Document type	Review ; Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1151092-4
ISSN	1473-6543 ; 1535-3842 ; 1062-4813 ; 1062-4821
ISSN (online)	1473-6543 ; 1535-3842
ISSN	1062-4813 ; 1062-4821
DOI	10.1097/MNH.0000000000000873
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Zs.A 3686: Show issues

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Article ; Online: Authors' Reply: Serum Protein-induced Tubular Injury.

Lidberg, Kevin / Himmelfarb, Jonathan / Kelly, Edward / Akilesh, Shreeram

Journal of the American Society of Nephrology : JASN

2022 Volume 33, Issue 8, Page(s) 1627–1628

MeSH term(s)	Albuminuria ; Blood Proteins ; Humans ; Kidney Tubules, Proximal ; Nephrotic Syndrome ; Proteinuria/chemically induced
Chemical Substances	Blood Proteins
Language	English
Publishing date	2022-06-15
Publishing country	United States
Document type	Letter ; Comment
ZDB-ID	1085942-1
ISSN	1533-3450 ; 1046-6673
ISSN (online)	1533-3450
ISSN	1046-6673
DOI	10.1681/ASN.2022060657
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Zs.A 3344: Show issues

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Article ; Online: Challenges and Opportunities for the Clinical Translation of Spatial Transcriptomics Technologies.

Smith, Kelly D / Prince, David K / MacDonald, James W / Bammler, Theo K / Akilesh, Shreeram

Glomerular diseases

2024 Volume 4, Issue 1, Page(s) 49–63

Abstract: Background: The first spatially resolved transcriptomics platforms, GeoMx (Nanostring) and Visium (10x Genomics) were launched in 2019 and were recognized as the method of the year by : Summary: In this review, we provide a description of the ... ...

Abstract	Background: The first spatially resolved transcriptomics platforms, GeoMx (Nanostring) and Visium (10x Genomics) were launched in 2019 and were recognized as the method of the year by Summary: In this review, we provide a description of the existing and emerging technologies that can be used to capture spatially resolved gene and protein expression data from tissue. These technologies have provided new insight into the spatial heterogeneity of diseases, how reactions to disease are distributed within a tissue, which cells are affected, and molecular pathways that predict disease and response to therapy. Key message: The upcoming years will see intense use of spatial transcriptomics technologies to better define the pathophysiology of kidney diseases and develop novel diagnostic tests to guide personalized treatments for patients.
Language	English
Publishing date	2024-03-13
Publishing country	Switzerland
Document type	Journal Article ; Review
ISSN	2673-3633
ISSN (online)	2673-3633
DOI	10.1159/000538344
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Article ; Online: Pathogenesis of coronavirus disease 2019-associated kidney injury.

Smith, Kelly D / Akilesh, Shreeram

Current opinion in nephrology and hypertension

2021 Volume 30, Issue 3, Page(s) 324–331

Abstract: Purpose of review: The current review summarizes the pathologic findings in kidneys from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients who have had autopsies or undergone biopsy, and the pathogenic mechanisms implicated ... ...

Abstract	Purpose of review: The current review summarizes the pathologic findings in kidneys from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients who have had autopsies or undergone biopsy, and the pathogenic mechanisms implicated in coronavirus disease 2019 (COVID-19)-associated kidney diseases. Recent findings: Direct infection of the kidney by SARS-CoV-2 is not common, and convincing morphologic evidence of substantive kidney infection by SARS-CoV-2 is lacking. Severe COVID-19-associated acute kidney injury is likely multifactorial and results from the physiologic disturbances and therapies used to treat this illness. COVID-19-associated collapsing glomerulopathy (COVAN) is seen almost exclusively in patients with apolipoprotein L1 high-risk genotypes with no evidence of direct infection of the kidney by SARS-CoV-2. Summary: The prevailing evidence does not support substantive or persistent infection of kidneys in COVID-19 and indirect means of tissue injury are favored, although a 'hit and run' model cannot be excluded. COVAN frequently occurs in patients with mild respiratory systems, suggesting that innate and adaptive immune responses to SARS-CoV-2 infection may provide the second hit needed for the development of collapsing glomerulopathy in susceptible individuals.
MeSH term(s)	Acute Kidney Injury/etiology ; COVID-19/complications ; Humans ; Kidney/pathology ; Kidney/virology ; SARS-CoV-2
Language	English
Publishing date	2021-05-04
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1151092-4
ISSN	1473-6543 ; 1535-3842 ; 1062-4813 ; 1062-4821
ISSN (online)	1473-6543 ; 1535-3842
ISSN	1062-4813 ; 1062-4821
DOI	10.1097/MNH.0000000000000708
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Article ; Online: Am I a coronavirus?

Smith, Kelly D / Akilesh, Shreeram / Alpers, Charles E / Nicosia, Roberto F

Kidney international

2020 Volume 98, Issue 2, Page(s) 506–507

MeSH term(s)	Betacoronavirus ; COVID-19 ; China ; Coronavirus ; Coronavirus Infections ; Humans ; Pandemics ; Pneumonia, Viral ; SARS-CoV-2
Keywords	covid19
Language	English
Publishing date	2020-06-04
Publishing country	United States
Document type	Letter ; Comment
ZDB-ID	120573-0
ISSN	1523-1755 ; 0085-2538
ISSN (online)	1523-1755
ISSN	0085-2538
DOI	10.1016/j.kint.2020.05.021
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Article: Single cell atlas of kidney cancer endothelial cells reveals distinct expression profiles and phenotypes.

Xu, Yuexin / Miller, Chris P / Xue, Jun / Zheng, Ying / Warren, Edus H / Tykodi, Scott S / Akilesh, Shreeram

Research square

2023

Abstract: Background: Tumor endothelial cells (TECs) represent the primary interface between the tumor microenvironment and circulating immune cells, however their phenotypes are incompletely understood in highly vascularized clear cell renal cell carcinoma ( ... ...

Abstract	Background: Tumor endothelial cells (TECs) represent the primary interface between the tumor microenvironment and circulating immune cells, however their phenotypes are incompletely understood in highly vascularized clear cell renal cell carcinoma (ccRCC). Methods: We purified tumor and matched normal endothelial cells (NECs) from ccRCC specimens and performed single-cell RNA-sequencing to create a reference-quality atlas available as a searchable web resource for gene expression patterns. We established paired primary TECs and NECs cultures for ex vivo functional testing. Results: TECs from multiple donors shared a common phenotype with increased expression of pathways related to extracellular matrix regulation, cell-cell communication, and insulin-like growth factor signaling that was conserved in comparison to hepatocellular carcinoma associated TECs, suggesting convergent TEC phenotypes between unrelated tumors. Cultured TECs stably maintained a core program of differentially regulated genes, were inherently resistant to apoptosis after vascular endothelial growth factor removal and displayed increased adhesiveness to subsets of immune cells including regulatory T-cells. Conclusions: Our studies delineate unique functional and phenotypic properties of TECs, which may provide insights into their interactions with available and emerging therapies. Functional phenotypes of cultured TECs suggest potential mechanisms of resistance to both antiangiogenic and immune-based therapies.
Language	English
Publishing date	2023-11-10
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-3558517/v1
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Article ; Online: Multi-omic analysis of human kidney tissue identified medulla-specific gene expression patterns.

Haug, Stefan / Muthusamy, Selvaraj / Li, Yong / Stewart, Galen / Li, Xianwu / Treppner, Martin / Köttgen, Anna / Akilesh, Shreeram

Kidney international

2023 Volume 105, Issue 2, Page(s) 293–311

Abstract: The kidney medulla is a specialized region with important homeostatic functions. It has been implicated in genetic and developmental disorders along with ischemic and drug-induced injuries. Despite its role in kidney function and disease, the medulla's ... ...

Abstract	The kidney medulla is a specialized region with important homeostatic functions. It has been implicated in genetic and developmental disorders along with ischemic and drug-induced injuries. Despite its role in kidney function and disease, the medulla's baseline gene expression and epigenomic signatures have not been well described in the adult human kidney. Here we generated and analyzed gene expression (RNA-seq), chromatin accessibility (ATAC-seq), chromatin conformation (Hi-C) and spatial transcriptomic data from the adult human kidney cortex and medulla. Tissue samples were obtained from macroscopically dissected cortex and medulla of tumor-adjacent normal material in nephrectomy specimens from five male patients. We used these carefully annotated specimens to reassign incorrectly labeled samples in the larger public Genotype-Tissue Expression (GTEx) Project, and to extract meaningful medullary gene expression signatures. Using integrated analysis of gene expression, chromatin accessibility and conformation profiles, we found insights into medulla development and function and then validated this by spatial transcriptomics and immunohistochemistry. Thus, our datasets provide a valuable resource for functional annotation of variants from genome-wide association studies and are freely accessible through an epigenome browser portal.
MeSH term(s)	Adult ; Humans ; Male ; Multiomics ; Genome-Wide Association Study ; Chromatin ; Kidney ; Transcriptome
Chemical Substances	Chromatin
Language	English
Publishing date	2023-11-22
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.2023.10.024
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Zs.A 797: Show issues

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Article ; Online: Therapeutic targeting of tumor spheroids in a 3D microphysiological renal cell carcinoma-on-a-chip system.

Miller, Chris P / Fung, Megan / Jaeger-Ruckstuhl, Carla A / Xu, Yuexin / Warren, Edus H / Akilesh, Shreeram / Tykodi, Scott S

Neoplasia (New York, N.Y.)

2023 Volume 46, Page(s) 100948

Abstract: Metastatic renal cell carcinoma (RCC) remains an incurable disease for most patients highlighting an urgent need for new treatments. However, the preclinical investigation of new therapies is limited by traditional two-dimensional (2D) cultures which do ... ...

Abstract	Metastatic renal cell carcinoma (RCC) remains an incurable disease for most patients highlighting an urgent need for new treatments. However, the preclinical investigation of new therapies is limited by traditional two-dimensional (2D) cultures which do not recapitulate the properties of tumor cells within a collagen extracellular matrix (ECM), while human tumor xenografts are time-consuming, expensive and lack adaptive immune cells. We report a rapid and economical human microphysiological system ("RCC-on-a-chip") to investigate therapies targeting RCC spheroids in a 3D collagen ECM. We first demonstrate that culture of RCC cell lines A498 and RCC4 in a 3D collagen ECM more faithfully reproduces the gene expression program of primary RCC tumors compared to 2D culture. We next used bortezomib as a cytotoxin to develop automated quantification of dose-dependent tumor spheroid killing. We observed that viable RCC spheroids exhibited collective migration within the ECM and demonstrated that our 3D system can be used to identify compounds that inhibit spheroid collective migration without inducing cell death. Finally, we demonstrate the RCC-on-a-chip as a platform to model the trafficking of tumor-reactive T cells into the ECM and observed antigen-specific A498 spheroid killing by engineered human CD8
MeSH term(s)	Humans ; Carcinoma, Renal Cell/drug therapy ; Carcinoma, Renal Cell/genetics ; Carcinoma, Renal Cell/metabolism ; Kidney Neoplasms/drug therapy ; Kidney Neoplasms/genetics ; Kidney Neoplasms/metabolism ; CD8-Positive T-Lymphocytes/metabolism ; Collagen ; Lab-On-A-Chip Devices ; Spheroids, Cellular/metabolism
Chemical Substances	Collagen (9007-34-5)
Language	English
Publishing date	2023-11-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	1483840-0
ISSN	1476-5586 ; 1522-8002
ISSN (online)	1476-5586
ISSN	1522-8002
DOI	10.1016/j.neo.2023.100948
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Zs.A 5203: Show issues

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Article ; Online: Immunohistochemical Detection of 5T4 in Renal Cell Carcinoma.

Miller, Christopher P / Shokri, Farinaz / Akilesh, Shreeram / Xu, Yuexin / Warren, Edus H / Tykodi, Scott S / Tretiakova, Maria

Applied immunohistochemistry & molecular morphology : AIMM

2023 Volume 31, Issue 3, Page(s) 135–144

Abstract: 5T4 (trophoblast glycoprotein encoded by TPBG ) is a cancer/testis antigen highly expressed in renal cell carcinoma (RCC) and many other cancers but rarely in normal tissues. Interest in developing 5T4 as a prognostic biomarker and direct targeting of ... ...

Abstract	5T4 (trophoblast glycoprotein encoded by TPBG ) is a cancer/testis antigen highly expressed in renal cell carcinoma (RCC) and many other cancers but rarely in normal tissues. Interest in developing 5T4 as a prognostic biomarker and direct targeting of 5T4 by emerging receptor-engineered cellular immunotherapies has been hampered by the lack of validated 5T4-specific reagents for immunohistochemistry (IHC). We tested 4 commercially available monoclonal antibodies (mAbs) for the detection of 5T4 in formalin-fixed, paraffin-embedded RCC and normal tissues. Using parental and TPBG -edited A498 cells, 3 mAbs showed 5T4 specificity. Further analyses focused on 2 mAbs with the most robust staining (MBS1750093, Ab134162). IHC on tissue microarrays incorporating 263 renal tumors showed high staining concordance of these 2 mAbs ranging from 0.80 in chromophobe RCC to 0.89 in advanced clear cell RCC (ccRCC). MBS1750093, the most sensitive, exhibited 2+/3+ staining in papillary RCC (92.2%) > advanced ccRCC (60.0%) > chromophobe RCC (43.6%) > localized ccRCC (39.6%) > oncocytoma (22.7%). RNA in situ hybridization also revealed high levels of TPBG RNA were present most frequently in papillary and advanced ccRCC. In advanced ccRCC, there was a trend towards higher 5T4 expression and regional or distant metastases. Normal organ controls showed no or weak staining with the exception of focal moderate staining in kidney glomeruli and distal tubules by IHC. These data identify mAbs suitable for detecting 5T4 in formalin-fixed, paraffin-embedded tissues and demonstrate both interpatient and histologic subtype heterogeneity. Our validated 5T4 IHC protocol will facilitate biomarker studies and support the therapeutic targeting of 5T4.
MeSH term(s)	Humans ; Biomarkers, Tumor/metabolism ; Carcinoma, Renal Cell/metabolism ; Carrier Proteins ; Formaldehyde ; Kidney Neoplasms/metabolism ; RNA ; Membrane Glycoproteins/metabolism
Chemical Substances	Biomarkers, Tumor ; Carrier Proteins ; Formaldehyde (1HG84L3525) ; RNA (63231-63-0) ; trophoblastic glycoprotein 5T4, human ; Membrane Glycoproteins
Language	English
Publishing date	2023-02-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1473273-7
ISSN	1533-4058 ; 1062-3345 ; 1541-2016
ISSN (online)	1533-4058
ISSN	1062-3345 ; 1541-2016
DOI	10.1097/PAI.0000000000001101
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