&lt;b&gt;Genetic background-dependent diversity in renal failure caused by the tensin2 gene deficiency in the &lt;/b&gt;&lt;b&gt;mouse &lt;/b&gt;

Sasaki, Hayato; Marusugi, Kiyoma; Kimura, Junko; Kitamura, Hiroshi; Nagasaki, Ken Ichi; Torigoe, Daisuke; Agui, Takashi; Sasaki, Nobuya

doi:10.2220/biomedres.36.323

Cited by 17 publications

(24 citation statements)

References 23 publications

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“…Loss of Tns2 results in proteinuria and FP effacement of podocytes : Because the original ICGN mouse is a spontaneous mutant derived from a closed colony of ICR mice, there is no control strain. The FVB/N strain has been identified as susceptible to the development of GS and CKD [ 33 ]. Thus, we previously created FVB.ICGN- Tns2 nph (FVB- Tns2 nph ) congenic mice.…”

Section: Resultsmentioning

confidence: 99%

Functional validation of tensin2 SH2-PTB domain by CRISPR/Cas9-mediated genome editing

Marusugi

Nakano

Sasaki

et al. 2016

The Journal of Veterinary Medical Science

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Podocytes are terminally differentiated and highly specialized cells in the glomerulus, and they form a crucial component of the glomerular filtration barrier. The ICGN mouse is a model of glomerular dysfunction that shows gross morphological changes in the podocyte foot process, accompanied by proteinuria. Previously, we demonstrated that proteinuria in ICR-derived glomerulonephritis mouse ICGN mice might be caused by a deletion mutation in the tensin2 (Tns2) gene (designated Tns2nph). To test whether this mutation causes the mutant phenotype, we created knockout (KO) mice carrying a Tns2 protein deletion in the C-terminal Src homology and phosphotyrosine binding (SH2-PTB) domains (designated Tns2ΔC) via CRISPR/Cas9-mediated genome editing. Tns2nph/Tns2ΔC compound heterozygotes and Tns2ΔC/Tns2ΔC homozygous KO mice displayed podocyte abnormalities and massive proteinuria similar to ICGN mice, indicating that these two mutations are allelic. Further, this result suggests that the SH2-PTB domain of Tns2 is required for podocyte integrity. Tns2 knockdown in a mouse podocyte cell line significantly enhanced actin stress fiber formation and cell migration. Thus, this study provides evidence that alteration of actin remodeling resulting from Tns2 deficiency causes morphological changes in podocytes and subsequent proteinuria.

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Section: Resultsmentioning

confidence: 99%

Functional validation of tensin2 SH2-PTB domain by CRISPR/Cas9-mediated genome editing

Marusugi

Nakano

Sasaki

et al. 2016

The Journal of Veterinary Medical Science

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“…Tns2 nph mice with an FVB genetic background (hereafter simply, Tns2 nph mice) were generated as described previously [22]. Tns2 ∆C mice with an FVB genetic background (hereafter simply, Tns2 ∆C mice) were generated by further backcrossing the previously described Tns2 ∆C mice [13] 7 times onto FVB for 11 generations in total.…”

Section: Animalsmentioning

confidence: 99%

“…The PFafixed paraffin sections (2 µm in thickness) were subjected to normal histological processes and stained with periodic acid-Schiff (PAS) solution. To quantify the severity of glomerular damage, we used a histological injury score as previously described [22], with a slight modification. We subdivided the severity of glomerular histopathology into seven stages characterized by the following observations: 0, no abnormality; 1, mild expansion of the mesangial matrix; 2, partial thickening of the gBM; 3, vascular stenosis (partial expansion of the mesangial matrix); 4, entire expansion of the mesangial matrix; 5, abnormal dilation of the capillary lumen; and 6, retraction and collapse of the glomerular tuft.…”

Section: Histologymentioning

confidence: 99%

“…Tns2-null mutant (called Tn-s2 nph ) mice develop renal failure caused by postnatal alterations in podocytes, although this occurs in a straindependent manner. Tns2 nph induces podocyte foot process effacement accompanied by glomerular basement membrane (gBM) thickening, and subsequent glomerular and tubulointerstitial injuries in iCgN, which is the original strain possessing the nph mutation, FVB/NJ (FVB) and DBa/2J strains, but only modest gBM thickening in C57BL/6J and 129 +Ter /SvJcl strains [15,16,22,27,28]. recently, to clarify the domain contributions, we have generated TNS2 C-terminal deletion mutant (designated Tns2 ∆C , Fig.…”

Section: Introductionmentioning

confidence: 99%

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Deletion of the Tensin2 SH2-PTB domain, but not the loss of its PTPase activity, induces podocyte injury in FVB/N mouse strain

et al. 2020

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Tensin2 (TNS2) is a focal adhesion-localized protein possessing N-terminal tandem protein tyrosine phosphatase (PTPase) and C2 domains, and C-terminal tandem Src homology 2 (SH2) and phosphotyrosine binding (PTB) domains. Genetic deletion of Tns2 in a susceptible murine strain leads to podocyte alterations after birth. To clarify the domain contributions to podocyte maintenance, we generated two Tns2-mutant mice with the genetic background of the susceptible FVB/NJ strain, Tns2 ∆C and Tns2 CS mice, carrying a SH2-PTB domain deletion and a PTPase domain inactivation, respectively. The Tns2 ∆C mice developed massive albuminuria, severe glomerular injury and podocyte alterations similarly to those in Tns2-deficient mice. In contrast, the Tns2 CS mice showed no obvious phenotypic abnormalities. These results indicate that the TNS2 SH2-PTB domain, but not its PTPase activity, plays a role in podocyte maintenance. Furthermore, in a podocyte cell line, the truncated TNS2 mutant lacking the SH2-PTB domain lost the ability to localize to focal adhesion. Taken together, these data suggest that TNS2 recruitment to focal adhesion is required to maintain postnatal podocytes on a susceptible genetic background.

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“…Tns2 is a multidomain protein that possesses C1, PTPase, SH2 and PTB domains, and is considered to mediate integrin-associated signaling cascades and regulate Akt signaling [ 8 – 11 ]. Despite its ubiquitous expression and predicted function, Tns2 deficiency results only in alterations in podocytes and subsequent glomerular and tubulointerstitial injuries [ 7 , 12 – 14 ]. In addition, the severity of the renal failure caused by Tns2 deficiency is strongly influenced by murine genetic background [ 11 , 14 – 16 ].…”

Section: Introductionmentioning

confidence: 99%

Mouse chromosome 2 harbors genetic determinants of resistance to podocyte injury and renal tubulointerstitial fibrosis

et al. 2016

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BackgroundTensin2 deficiency results in alterations in podocytes and subsequent glomerular and tubulointerstitial injuries. However, this pathology is critically dependent on genetic background. While the Tensin2-deficient podocytes of resistant murine strains, including C57BL/6J mice, remain almost intact, susceptible murine strains with Tensin2 deficency, including ICGN mice, develop chronic kidney disease following alterations in the podocyte foot processes. In a previous study, genome-wide linkage analysis was utilized to identify the quantitative trait loci associated with the disease phenotypes on mouse chromosome 2. This study investigated the disease phenotypes of chromosome 2 consomic and subcongenic strains.ResultsICGN consomic mice introgressed with chromosome 2 from the C57BL/6J mouse were generated and found to exhibit milder renal failure than that in ICGN mice. We developed 6 subcongenic strains that carry C57BL/6J-derived chromosomal segments from the consomic strain. One showed significantly milder albuminuria, another showed significantly milder tubulointerstitial injury, and the both showed significantly milder glomerular injury.ConclusionsThese data indicate that mouse chromosome 2 harbors two major genes associated with the severities of nephropathy induced by Tensin2 deficiency. The proximal region on chromosome 2 contributes to the resistance to tubulointerstitial fibrosis. In contrast, the distal region on chromosome 2 contributes to the resistance to podocyte injury. This study would be helpful to discover the biological mechanism underlying the renal injury, and may lead to the identification of therapeutic targets.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-016-0378-1) contains supplementary material, which is available to authorized users.

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<b>Genetic background-dependent diversity in renal failure caused by the tensin2 gene deficiency in the </b><b>mouse </b>

Cited by 17 publications

References 23 publications

Functional validation of tensin2 SH2-PTB domain by CRISPR/Cas9-mediated genome editing

Functional validation of tensin2 SH2-PTB domain by CRISPR/Cas9-mediated genome editing

Deletion of the Tensin2 SH2-PTB domain, but not the loss of its PTPase activity, induces podocyte injury in FVB/N mouse strain

Mouse chromosome 2 harbors genetic determinants of resistance to podocyte injury and renal tubulointerstitial fibrosis

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