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

Namba, Masumi; Kobayashi, Tomoe; Kohno, Mayumi; Koyano, Takayuki; Hirose, Takuo; Fukushima, M.; Matsuyama, Makoto

doi:10.1038/s41598-021-00354-y

Cited by 8 publications

(9 citation statements)

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“…These results are consistent with previous reports that found no sex difference of renal disease progression in Col4a3 -/- mice on a 129/SvJ background [ 64 ]. Female Col4a3 -/- mice on C57Bl/6 and Balb/C backgrounds trended towards more severe phenotypes compared with males, consistent with work that described sex differences [ 62 , 64 , 65 ]. Blood pressure analyses indicated significantly increased SBP of male and female Col4a3 -/- mice only on a 129x1/SvJ background and significantly increased DBP only in Col4a3 -/- -129x1/SvJ females ( Figure 4 ).…”

Section: Discussionsupporting

confidence: 85%

“…As expected, all three strains of mice displayed decreased glomerular function as indicated by increased plasma BUN and creatinine ( Figure 7 ), defining characteristics of AS [ 13 , 62 ]. Whereas relatively minor differences could be attributed to genetic background or sex, a significant feature of BUN and creatinine expression was the large variation within each AS group relative to the tight grouping of wild types.…”

Section: Discussionmentioning

confidence: 73%

“…Murata et al, [ 63 ] reported similar findings with respect to collagen gene expression, and further described expression of α5/α6 (IV) chains in the GBM of autosomal recessive patients with homozygous mutations in COL4A4, suggesting relevance of the condition to human AS. A rat Col4a5 deficiency model that conferred severe AS symptoms with rapid progression expressed no α3/α4(IV) or α5/α6(IV) but normal expression of α1/α2(IV) [ 62 ], similar to human AS where α1/α2(IV) is unaffected or increased by AS Col4 mutations [ 1 ]. Taken together, the results suggest that augmented deposition of alternate α-IV chains in Col4a3 -/- mice does not contribute to the control of genetic background on AS severity.…”

Section: Discussionmentioning

confidence: 99%

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Col4a3-/- Mice on Balb/C Background Have Less Severe Cardiorespiratory Phenotype and SGLT2 Over-Expression Compared to 129x1/SvJ and C57Bl/6 Backgrounds

Irion

Williams

Capcha

et al. 2022

IJMS

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Alport syndrome (AS) is a hereditary renal disorder with no etiological therapy. In the preclinical Col4a3-/- model of AS, disease progression and severity vary depending on mouse strain. The sodium-glucose cotransporter 2 (SGLT2) is emerging as an attractive therapeutic target in cardiac/renal pathologies, but its application to AS remains untested. This study investigates cardiorespiratory function and SGLT2 renal expression in Col4a3-/- mice from three different genetic backgrounds, 129x1/SvJ, C57Bl/6 and Balb/C. male Col4a3-/- 129x1/SvJ mice displayed alterations consistent with heart failure with preserved ejection fraction (HFpEF). Female, but not male, C57Bl/6 and Balb/C Col4a3-/- mice exhibited mild changes in systolic and diastolic function of the heart by echocardiography. Male C57Bl/6 Col4a3-/- mice presented systolic dysfunction by invasive hemodynamic analysis. All strains except Balb/C males demonstrated alterations in respiratory function. SGLT2 expression was significantly increased in AS compared to WT mice from all strains. However, cardiorespiratory abnormalities and SGLT2 over-expression were significantly less in AS Balb/C mice compared to the other two strains. Systolic blood pressure was significantly elevated only in mutant 129x1/SvJ mice. The results provide further evidence for strain-dependent cardiorespiratory and hypertensive phenotype variations in mouse AS models, corroborated by renal SGLT2 expression, and support ongoing initiatives to develop SGLT2 inhibitors for the treatment of AS.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

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Col4a3-/- Mice on Balb/C Background Have Less Severe Cardiorespiratory Phenotype and SGLT2 Over-Expression Compared to 129x1/SvJ and C57Bl/6 Backgrounds

Irion

Williams

Capcha

et al. 2022

IJMS

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“…Although SD rats used in this study did not have a thrombus phenotype during the experiment, a preliminary examination of our renal congestion model using C57BL6, FVB, CBA, and DBA mice showed a high mortality rate within one day with thrombus formation. The genetic background of the experimental animals also affects the disease development and progression in several renal disease models [ 61 – 63 ]. Taken together with these points, the experimental design needs to be carefully determined by the species, strain, and IVC pressure maintenance necessities.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of platelet-derived growth factor pathway suppresses tubulointerstitial injury in renal congestion

Matsuki

Hirose

Ohsaki

et al. 2022

Journal of Hypertension

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Objective: Increased central venous pressure in congestive heart failure is responsible for renal dysfunction, which is mediated by renal venous congestion. Pericyte detachment from capillaries after renal congestion might trigger renal fibrogenesis via pericyte-myofibroblast transition (PMT). Platelet-derived growth factor receptors (PDGFRs), which are PMT indicators, were upregulated in our recently established renal congestion model. This study was designed to determine whether inhibition of the PDGFR pathway could suppress tubulointerstitial injury after renal congestion. Methods: The inferior vena cava between the renal veins was ligated in male Sprague-Dawley rats, inducing congestion only in the left kidney. Imatinib mesylate or vehicle were injected intraperitoneally daily from 1 day before the operation. Three days after the surgery, the effect of imatinib was assessed by physiological, morphological and molecular methods. The inhibition of PDGFRs against transforming growth factor-β1 (TGFB1)-induced fibrosis was also tested in human pericyte cell culture. Results: Increased kidney weight and renal fibrosis were observed in the congested kidneys. Upstream inferior vena cava (IVC) pressure immediately increased to around 20 mmHg after IVC ligation in both the imatinib and saline groups. Although vasa recta dilatation and pericyte detachment under renal congestion were maintained, imatinib ameliorated the increased kidney weight and suppressed renal fibrosis around the vasa recta. TGFB1-induced elevation of fibrosis markers in human pericytes was suppressed by PDGFR inhibitors at the transcriptional level. Conclusion: The activation of the PDGFR pathway after renal congestion was responsible for renal congestion-induced fibrosis. This mechanism could be a candidate therapeutic target for renoprotection against renal congestion-induced tubulointerstitial injury.

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“…Mutations in COL4A3, COL4A4, and COL4A5 have been detected in patients with AS. COL4A5 variants account as the causative reasons for more than 85% of AS patients (Namba et al, 2021;Pirson, 1999). In addition, studies have revealed that patients with heterozygous mutations in either COL4A3 or COL4A4 have a mild phenotype that causes hematuria and proteinuria and do not suffer from hearing loss or ocular defects (Savige et al, 2003;Fan et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Novel heterozygous mutation in COL4A4 responsible for Alport syndrome in a Chinese family

Liu

et al. 2022

Front. Genet.

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Background: Chronic kidney disease, a global public health problem, results in kidney damage or a gradual decline in the glomerular filtration rate. Alport syndrome is commonly characterized by chronic glomerulonephritis caused by a structural disorder in the glomerular basement membrane. Currently, three disease-causing genes, namely collagen type IV alpha 3–5 (COL4A3, COL4A4, and COL4A5), have been associated with the occurrence of Alport syndrome.Methods: We enrolled a Chinese family where the affected individuals suffered from recurrent hematuria and proteinuria. The proband was selected for whole-exome sequencing to identify the pathogenic mutations in this family.Results: After data filtering, a novel heterozygous COL4A4 variant (NM_000092: c.853G>A/p. G285A) was identified as the putative genetic lesion in the affected individuals. Further co-segregation analysis using Sanger sequencing confirmed that this novel COL4A4 mutation (c.853G>A/p. G285A) exists only in the affected individuals and is absent in other healthy family members as well as in the control cohort of 200 individuals from the same locality. According to American College of Medical Genetics and Genomics guidelines, the mutation was classified as ‘potentially pathogenic’. A bioinformatics-based prediction analysis revealed that this mutation is pathogenic and may disrupt the structure and function of type IV collagen. This variant is located at an evolutionarily conserved site of COL4A4.Conclusion: In this study, we identified a novel heterozygous COL4A4 variant (c.853G>A) in a Chinese AS family and assisted to diagnose this AS proband as autosomal-dominant Alport syndrome (ADAS). Our study expands the spectrum of Alport syndrome mutations and contributes to the genetic counseling and diagnosis of patients with Alport syndrome.

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

Cited by 8 publications

References 50 publications

Col4a3-/- Mice on Balb/C Background Have Less Severe Cardiorespiratory Phenotype and SGLT2 Over-Expression Compared to 129x1/SvJ and C57Bl/6 Backgrounds

Col4a3-/- Mice on Balb/C Background Have Less Severe Cardiorespiratory Phenotype and SGLT2 Over-Expression Compared to 129x1/SvJ and C57Bl/6 Backgrounds

Inhibition of platelet-derived growth factor pathway suppresses tubulointerstitial injury in renal congestion

Novel heterozygous mutation in COL4A4 responsible for Alport syndrome in a Chinese family

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