Trophoblast Glycoprotein: Possible Candidate Mediating Podocyte Injuries in Glomerulonephritis

Murakami, Taichi; Abe, Hideharu; Nagai, Kojiro; Tominaga, Tatsuya; Takamatsu, Norimichi; Araoka, Toshikazu; Kishi, Seiji; Takahashi, Tomohiro; Mima, Akira; Takai, Yoshimi; Kopp, Jeffrey B.; Doi, Toshio

doi:10.1159/000321366

Cited by 5 publications

(5 citation statements)

References 64 publications

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“…This preliminary interrogation, whilst not definitive or taking into account the potential effect of copy number variations, revealed some interesting findings. The analysis revealed several relevant polymorphisms in the linkage region on chromosome 9 (Table S2) including: Adamts7 , associated with inflammatory damage in elderly mice 45 and Tpbg , previously associated with glomerulonephritis 46 . However, the most significant result was a missense polymorphism in myosin 1e ( Myo1e ) resulting in a protein sequence difference at position 73 with a valine residue in C57BL/6J and an isoleucine in the other three strains.…”

Section: Discussionmentioning

confidence: 99%

Modification of an aggressive model of Alport Syndrome reveals early differences in disease pathogenesis due to genetic background

Falcone

Wisby

Nicol

et al. 2019

Sci Rep

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The link between mutations in collagen genes and the development of Alport Syndrome has been clearly established and a number of animal models, including knock-out mouse lines, have been developed that mirror disease observed in patients. However, it is clear from both patients and animal models that the progression of disease can vary greatly and can be modified genetically. We have identified a point mutation in Col4a4 in mice where disease is modified by strain background, providing further evidence of the genetic modification of disease symptoms. Our results indicate that C57BL/6J is a protective background and postpones end stage renal failure from 7 weeks, as seen on a C3H background, to several months. We have identified early differences in disease progression, including expression of podocyte-specific genes and podocyte morphology. In C57BL/6J mice podocyte effacement is delayed, prolonging normal renal function. The slower disease progression has allowed us to begin dissecting the pathogenesis of murine Alport Syndrome in detail. We find that there is evidence of differential gene expression during disease on the two genetic backgrounds, and that disease diverges by 4 weeks of age. We also show that an inflammatory response with increasing MCP-1 and KIM-1 levels precedes loss of renal function.

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Section: Discussionmentioning

confidence: 99%

Modification of an aggressive model of Alport Syndrome reveals early differences in disease pathogenesis due to genetic background

Falcone

Wisby

Nicol

et al. 2019

Sci Rep

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“…The extracellular domain contains seven leucine-rich repeats (LRRs) clustered in two LRR domains. TPBG functions in cell adhesion and migration and is associated with the epithelial–mesenchymal transition (EMT), a process that occurs during development and tumor metastasis. − The promigratory functions of TPBG along with its interaction with the cytoskeleton manifest in the promotion of renal podocyte motility, the modulation of chemotaxis and cell signaling mediated by the CXCL12-CXCR4 axis, , and the regulation of activity-dependent dendritic development in the olfactory bulb . In zebrafish embryos, TPBG regulates Wnt pathway selection in signal receiving cells by acting as a feedback inhibitor of canonical Wnt signaling while enhancing noncanonical Wnt signaling …”

Section: Introductionmentioning

confidence: 99%

Phenotype of TPBG Gene Replacement in the Mouse and Impact on the Pharmacokinetics of an Antibody–Drug Conjugate

Leal

Lin

et al. 2014

Mol. Pharmaceutics

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The use of predictive preclinical models in drug discovery is critical for compound selection, optimization, preclinical to clinical translation, and strategic decision-making. Trophoblast glycoprotein (TPBG), also known as 5T4, is the therapeutic target of several anticancer agents currently in clinical development, largely due to its high expression in tumors and low expression in normal adult tissues. In this study, mice were engineered to express human TPBG under endogenous regulatory sequences by replacement of the murine Tpbg coding sequence. The gene replacement was considered functional since the hTPBG knockin (hTPBG-KI) mice did not exhibit clinical observations or histopathological phenotypes that are associated with Tpbg gene deletion, except in rare instances. The expression of hTPBG in certain epithelial cell types and in different microregions of the brain and spinal cord was consistent with previously reported phenotypes and expression patterns. In pharmacokinetic studies, the exposure of a clinical-stage anti-TPBG antibody-drug conjugate (ADC), A1mcMMAF, was lower in hTPBG-KI versus wild-type animals, which was evidence of target-related increased clearance in hTPBG-KI mice. Thus, the hTPBG-KI mice constitute an improved system for pharmacology studies with current and future TPBG-targeted therapies and can generate more precise pharmacokinetic and pharmacodynamic data. In general the strategy of employing gene replacement to improve pharmacokinetic assessments should be broadly applicable to the discovery and development of ADCs and other biotherapeutics.

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“…Regarding possible functions, 5T4 upregulation in injured podocytes enhanced motility and was suggested to be involved in cytoskeletal rearrangements in a rat model of proliferative glomerulonephritis. 42 In summary, we have identified specific mAbs for the detection of 5T4 by IHC in FFPE renal tumors and demonstrated both interpatient and histologic subtype heterogeneity in 5T4 expression levels. These reagents will facilitate future correlative studies of 5T4 expression with RCC patient outcomes and allow pretreatment patient selection for adoptive T-cell immunotherapy trials with engineered T cells targeting 5T4 in RCC.…”

Section: Discussionmentioning

confidence: 77%

“…Thus, although the basis for the disparate findings regarding 5T4 expression in the normal kidney across different studies remains unknown, clinical studies targeting 5T4 to date (albeit with limited efficacy) have not reported signs of off-target toxicity in the normal kidney. Regarding possible functions, 5T4 upregulation in injured podocytes enhanced motility and was suggested to be involved in cytoskeletal rearrangements in a rat model of proliferative glomerulonephritis 42…”

Section: Discussionmentioning

confidence: 99%

Immunohistochemical Detection of 5T4 in Renal Cell Carcinoma

Miller

Shokri²,

Akilesh³

et al. 2023

Applied Immunohistochemistry &Amp; Molecular Morphology

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and M.T.: designed the study; C.P.M.: performed the gene editing and T-cell cytotoxicity; F.S. and M.T.: compiled the tissue microarrays and performed the IHC; M.T.: performed the scoring of IHC and RNA in situ hybridization; M.T. and S.A.: provided expert pathology interpretation; S.A.: performed the RNA in situ hybridization; Y.X.: performed the Kaplan-Meier analysis; C.P.M. and M.T.: performed the data analysis and prepared the figures; C.P.M.: wrote the manuscript; C.

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Trophoblast Glycoprotein: Possible Candidate Mediating Podocyte Injuries in Glomerulonephritis

Cited by 5 publications

References 64 publications

Modification of an aggressive model of Alport Syndrome reveals early differences in disease pathogenesis due to genetic background

Modification of an aggressive model of Alport Syndrome reveals early differences in disease pathogenesis due to genetic background

Phenotype of TPBG Gene Replacement in the Mouse and Impact on the Pharmacokinetics of an Antibody–Drug Conjugate

Immunohistochemical Detection of 5T4 in Renal Cell Carcinoma

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