Bidirectional, non-necrotizing glomerular crescents are the critical pathology in X-linked Alport syndrome mouse model harboring nonsense mutation of human COL4A5

Song, Jiang Ying; Saga, Nobuyuki; Kawanishi, Kunio; Hashikami, Kentaro; Takeyama, Michiyasu; Nagata, Michio

doi:10.1038/s41598-020-76068-4

Cited by 6 publications

(6 citation statements)

References 36 publications

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“…In the past decades, several Alport syndrome animal models have been produced in mouse. The mutant mice for Col4 α 3 , Col4 α 4 , and Col4 α 5 are developed and well characterized 7 – 12 . These model mice led important aspects of the renal disease.…”

Section: Introductionmentioning

confidence: 99%

Creation of X-linked Alport syndrome rat model with Col4a5 deficiency

Namba

Kobayashi

Kohno

et al. 2021

Sci Rep

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Alport syndrome is an inherited chronic human kidney disease, characterized by glomerular basement membrane abnormalities. This disease is caused by mutations in COL4A3, COL4A4, or COL4A5 gene. The knockout mice for Col4α3, Col4α4, and Col4α5 are developed and well characterized for the study of Alport syndrome. However, disease progression and effects of pharmacological therapy depend on the genetic variability. This model was reliable only to mouse. In this study, we created a novel Alport syndrome rat model utilizing the rGONAD technology, which generated rat with a deletion of the Col4α5 gene. Col4α5 deficient rats showed hematuria, proteinuria, high levels of BUN, Cre, and then died at 18 to 28 weeks of age (Hemizygous mutant males). Histological and ultrastructural analyses displayed the abnormalities including parietal cell hyperplasia, mesangial sclerosis, and interstitial fibrosis. Then, we demonstrated that α3/α4/α5 (IV) and α5/α5/α6 (IV) chains of type IV collagen disrupted in Col4α5 deficient rats. Thus, Col4α5 mutant rat is a reliable candidate for the Alport syndrome model for underlying the mechanism of kidney diseases and further identifying potential therapeutic targets for human renal diseases.

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Section: Introductionmentioning

confidence: 99%

Creation of X-linked Alport syndrome rat model with Col4a5 deficiency

Namba

Kobayashi

Kohno

et al. 2021

Sci Rep

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“…In addition, glomerular crescents were noticed in Del-ATGG male mice, which was not observed in the patient, probably because the size of the patient’s renal tissue biopsy was limited. Crescents is an uncommon histological manifestation of AS, could be detected in 20% of AS patient, and occasionally found in other AS animal models, such as G471X mice model and autosomal dominant hereditary bull terrier AS model ( 16 – 18 ). But the formation mechanism of the crescents needs to be further studied.…”

Section: Discussionmentioning

confidence: 99%

A mouse model for X-linked Alport syndrome induced by Del-ATGG in the Col4a5 gene

Zhang²,

Cui³

et al. 2023

Front. Med.

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Alport syndrome (AS) is an inherited glomerular basement membrane (GBM) disease leading to end-stage renal disease (ESRD). X-linked AS (XLAS) is caused by pathogenic variants in the COL4A5 gene. Many pathogenic variants causing AS have been detected, but the genetic modifications and pathological alterations leading to ESRD have not been fully characterized. In this study, a novel frameshift variant c.980_983del ATGG in the exon 17 of the COL4A5 gene detected in a patient with XLAS was introduced into a mouse model in by CRISPR/Cas9 system. Through biochemical urinalysis, histopathology, immunofluorescence, and transmission electron microscopy (TEM) detection, the clinical manifestations and pathological alterations of Del-ATGG mice were characterized. From 16 weeks of age, obvious proteinuria was observed and TEM showed typical alterations of XLAS. The pathological changes included glomerular atrophy, increased monocytes in renal interstitial, and the absence of type IV collagen α5. The expression of Col4a5 was significantly decreased in Del-ATGG mouse model. Transcriptomic analysis showed that differentially expressed genes (DEGs) accounted for 17.45% (4,188/24003) of all genes. GO terms indicated that the functions of identified DEGs were associated with cell adhesion, migration, and proliferation, while KEGG terms found enhanced the degradation of ECM, amino acid metabolism, helper T-cell differentiation, various receptor interactions, and several important pathways such as chemokine signaling pathway, NF-kappa B signaling pathway, JAK–STAT signaling pathway. In conclusion, a mouse model with a frameshift variant in the Col4a5 gene has been generated to demonstrate the biochemical, histological, and pathogenic alterations related to AS. Further gene expression profiling and transcriptomic analysis revealed DEGs and enriched pathways potentially related to the disease progression of AS. This Del-ATGG mouse model could be used to further define the genetic modifiers and potential therapeutic targets for XLAS treatment.

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“…Col4a4 m1H is characterized by a reduced weight at approximately 1.5 months (5 weeks). Body weight of hemizygous Col4a5 em1Keha males appears normal until 14 weeks of age with a slower gain as compared to wild-type mice after 16 weeks [ 30 ], but when examined at 24 weeks, the body weight of these mice is reduced compared to the wild type [ 42 ]. In the Col4a3 p.G1332E , body weight is gradually decreased from 6 months onward (Odiatis and Deltas—unpublished results).…”

Section: Comparison Of Sex Morphological and Physiological Characteri...mentioning

confidence: 99%

“…At this advanced age, there is widespread glomerular tuft collapse with thickened Bowman’s capsule, parietal cell hyperplasia, increased mesangial matrices, and increasing glomerular enlargement in parallel with increasing glomerulosclerosis. Expression of Col4a5 is not detected either in glomeruli or tubules [ 30 , 42 ].…”

Section: Comparison Of Glomerular Alterationsmentioning

confidence: 99%

A Comparative Presentation of Mouse Models That Recapitulate Most Features of Alport Syndrome

Nikolaou

Deltas

2022

Genes

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Alport syndrome is a hereditary kidney disease caused by mutations in the three genes encoding for collagen IV: COL4A3, COL4A4, and COL4A5. Several mouse models have been created for the study of this disease with variable phenotypic outcomes. This review is an up-to-date presentation of the current mouse models existing in the literature with a detailed comparison of the phenotypic features characterizing each model. Although in humans it is primarily a glomerulopathy, data suggest that in some mouse models, the initial symptoms appear in the tubule-interstitial region rather than the glomerulus. Additionally, in some other models, the severity of disease in the tubule-interstitial region is affected by the genetic background. In conclusion, the phenotypic spectrum of each model appears to be affected by the model’s genetic background, the position of the genetic alteration within the gene, and the type of the genetic alteration. Despite these disparities, mouse models recapitulate with relatively high fidelity several features of the human disease, which makes them useful for studies aimed at better understanding cellular pathomechanisms and for finding new treatments.

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Bidirectional, non-necrotizing glomerular crescents are the critical pathology in X-linked Alport syndrome mouse model harboring nonsense mutation of human COL4A5

Cited by 6 publications

References 36 publications

Creation of X-linked Alport syndrome rat model with Col4a5 deficiency

Creation of X-linked Alport syndrome rat model with Col4a5 deficiency

A mouse model for X-linked Alport syndrome induced by Del-ATGG in the Col4a5 gene

A Comparative Presentation of Mouse Models That Recapitulate Most Features of Alport Syndrome

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