Podocyte-specific Crb2 knockout mice develop focal segmental glomerulosclerosis
Abstract Crb2 is a cell polarity-related type I transmembrane protein expressed in the apical membrane of podocytes. Knockdown of crb2 causes glomerular permeability defects in zebrafish, and its complete knockout causes embryonic lethality in mice. There are also reports of Crb2 mutations in patien...
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| Format: | Article |
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Nature Portfolio
2021-10-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-00159-z |
| _version_ | 1818585676358090752 |
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| author | Akiko Tanoue Kan Katayama Yugo Ito Kensuke Joh Masaaki Toda Taro Yasuma Corina N. D’Alessandro-Gabazza Hiroshi Kawachi Kunimasa Yan Masaaki Ito Esteban C. Gabazza Karl Tryggvason Kaoru Dohi |
| author_facet | Akiko Tanoue Kan Katayama Yugo Ito Kensuke Joh Masaaki Toda Taro Yasuma Corina N. D’Alessandro-Gabazza Hiroshi Kawachi Kunimasa Yan Masaaki Ito Esteban C. Gabazza Karl Tryggvason Kaoru Dohi |
| author_sort | Akiko Tanoue |
| collection | DOAJ |
| description | Abstract Crb2 is a cell polarity-related type I transmembrane protein expressed in the apical membrane of podocytes. Knockdown of crb2 causes glomerular permeability defects in zebrafish, and its complete knockout causes embryonic lethality in mice. There are also reports of Crb2 mutations in patients with steroid-resistant nephrotic syndrome, although the precise mechanism is unclear. The present study demonstrated that podocyte-specific Crb2 knockout mice develop massive albuminuria and microhematuria 2-month after birth and focal segmental glomerulosclerosis and tubulointerstitial fibrosis with hemosiderin-laden macrophages at 6-month of age. Transmission and scanning electron microscopic studies demonstrated injury and foot process effacement of podocytes in 6-month aged podocyte-specific Crb2 knockout mice. The number of glomerular Wt1-positive cells and the expressions of Nphs2, Podxl, and Nphs1 were reduced in podocyte-specific Crb2 knockout mice compared to negative control mice. Human podocytes lacking CRB2 had significantly decreased F-actin positive area and were more susceptible to apoptosis than their wild-type counterparts. Overall, this study's results suggest that the specific deprivation of Crb2 in podocytes induces altered actin cytoskeleton reorganization associated with dysfunction and accelerated apoptosis of podocytes that ultimately cause focal segmental glomerulosclerosis. |
| first_indexed | 2024-12-16T08:40:51Z |
| format | Article |
| id | doaj.art-3d737ece5bb54aff9534bd7cdc927461 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-16T08:40:51Z |
| publishDate | 2021-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-3d737ece5bb54aff9534bd7cdc9274612022-12-21T22:37:41ZengNature PortfolioScientific Reports2045-23222021-10-0111111610.1038/s41598-021-00159-zPodocyte-specific Crb2 knockout mice develop focal segmental glomerulosclerosisAkiko Tanoue0Kan Katayama1Yugo Ito2Kensuke Joh3Masaaki Toda4Taro Yasuma5Corina N. D’Alessandro-Gabazza6Hiroshi Kawachi7Kunimasa Yan8Masaaki Ito9Esteban C. Gabazza10Karl Tryggvason11Kaoru Dohi12Department of Cardiology and Nephrology, Mie University Graduate School of MedicineDepartment of Cardiology and Nephrology, Mie University Graduate School of MedicineDepartment of Medical Biochemistry and Biophysics, Karolinska InstituteDepartment of Pathology, The Jikei University School of MedicineDepartment of Immunology, Mie University Graduate School of MedicineDepartment of Immunology, Mie University Graduate School of MedicineDepartment of Immunology, Mie University Graduate School of MedicineDepartment of Cell Biology, Kidney Research Center, Niigata University Graduate School of Medical and Dental SciencesDepartment of Pediatrics, Kyorin University School of MedicineDepartment of Cardiology and Nephrology, Mie University Graduate School of MedicineDepartment of Immunology, Mie University Graduate School of MedicineDepartment of Medical Biochemistry and Biophysics, Karolinska InstituteDepartment of Cardiology and Nephrology, Mie University Graduate School of MedicineAbstract Crb2 is a cell polarity-related type I transmembrane protein expressed in the apical membrane of podocytes. Knockdown of crb2 causes glomerular permeability defects in zebrafish, and its complete knockout causes embryonic lethality in mice. There are also reports of Crb2 mutations in patients with steroid-resistant nephrotic syndrome, although the precise mechanism is unclear. The present study demonstrated that podocyte-specific Crb2 knockout mice develop massive albuminuria and microhematuria 2-month after birth and focal segmental glomerulosclerosis and tubulointerstitial fibrosis with hemosiderin-laden macrophages at 6-month of age. Transmission and scanning electron microscopic studies demonstrated injury and foot process effacement of podocytes in 6-month aged podocyte-specific Crb2 knockout mice. The number of glomerular Wt1-positive cells and the expressions of Nphs2, Podxl, and Nphs1 were reduced in podocyte-specific Crb2 knockout mice compared to negative control mice. Human podocytes lacking CRB2 had significantly decreased F-actin positive area and were more susceptible to apoptosis than their wild-type counterparts. Overall, this study's results suggest that the specific deprivation of Crb2 in podocytes induces altered actin cytoskeleton reorganization associated with dysfunction and accelerated apoptosis of podocytes that ultimately cause focal segmental glomerulosclerosis.https://doi.org/10.1038/s41598-021-00159-z |
| spellingShingle | Akiko Tanoue Kan Katayama Yugo Ito Kensuke Joh Masaaki Toda Taro Yasuma Corina N. D’Alessandro-Gabazza Hiroshi Kawachi Kunimasa Yan Masaaki Ito Esteban C. Gabazza Karl Tryggvason Kaoru Dohi Podocyte-specific Crb2 knockout mice develop focal segmental glomerulosclerosis Scientific Reports |
| title | Podocyte-specific Crb2 knockout mice develop focal segmental glomerulosclerosis |
| title_full | Podocyte-specific Crb2 knockout mice develop focal segmental glomerulosclerosis |
| title_fullStr | Podocyte-specific Crb2 knockout mice develop focal segmental glomerulosclerosis |
| title_full_unstemmed | Podocyte-specific Crb2 knockout mice develop focal segmental glomerulosclerosis |
| title_short | Podocyte-specific Crb2 knockout mice develop focal segmental glomerulosclerosis |
| title_sort | podocyte specific crb2 knockout mice develop focal segmental glomerulosclerosis |
| url | https://doi.org/10.1038/s41598-021-00159-z |
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