<i>SHROOM3</i> Deficiency Aggravates Adriamycin-Induced Nephropathy Accompanied by Focal Adhesion Disassembly and Stress Fiber Disorganization
<i>SHROOM3</i> encodes an actin-binding protein involved in kidney development and has been associated with chronic kidney disease through genome-wide association studies. However, its regulatory role in proteinuric kidney diseases and its mechanistic contributions to podocyte homeostasi...
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2025-06-01
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| author | Li-Nan Xu Ying-Ying Sun Yan-Feng Tan Xin-Yue Zhou Tian-Chao Xiang Ye Fang Fei Li Qian Shen Hong Xu Jia Rao |
| author_facet | Li-Nan Xu Ying-Ying Sun Yan-Feng Tan Xin-Yue Zhou Tian-Chao Xiang Ye Fang Fei Li Qian Shen Hong Xu Jia Rao |
| author_sort | Li-Nan Xu |
| collection | DOAJ |
| description | <i>SHROOM3</i> encodes an actin-binding protein involved in kidney development and has been associated with chronic kidney disease through genome-wide association studies. However, its regulatory role in proteinuric kidney diseases and its mechanistic contributions to podocyte homeostasis remain poorly defined. Here, we analyzed single-cell transcriptomic datasets and the Nephroseq database to delineate <i>SHROOM3</i> expression patterns in proteinuric kidney diseases. Using podocyte-specific <i>SHROOM3</i> knockout mice and an Adriamycin (ADR)-induced nephropathy mouse model, we demonstrated that glomerular <i>SHROOM3</i>, specifically in podocytes, was upregulated following ADR treatment during the acute injury phase but downregulated in chronic kidney disease. Clinically, the glomerular <i>SHROOM3</i> expression positively correlated with glomerular filtration rates in focal segmental glomerulosclerosis patients. Genetic ablation of <i>SHROOM3</i> in podocytes exacerbated ADR-induced proteinuria, diminished podocyte markers (nephrin, podocin, and WT1), and accelerated glomerulosclerosis. In vitro, <i>SHROOM3</i> deficiency impaired podocyte size and adhesion, concomitant with the downregulation of focal adhesion molecules (talin1, vinculin, and paxillin) and stress fiber regulators (synaptopodin and RhoA), as well as calpain activation and RhoA inactivation. Our findings reveal a critical role for <i>SHROOM3</i> in maintaining podocyte integrity and suggest its therapeutic potential in mitigating proteinuric kidney disease progression. |
| format | Article |
| id | doaj-art-be804907e46f40e487734b4e12f5f74c |
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| issn | 2073-4409 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | MDPI AG |
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| series | Cells |
| spelling | doaj-art-be804907e46f40e487734b4e12f5f74c2025-06-25T13:36:36ZengMDPI AGCells2073-44092025-06-01141289510.3390/cells14120895<i>SHROOM3</i> Deficiency Aggravates Adriamycin-Induced Nephropathy Accompanied by Focal Adhesion Disassembly and Stress Fiber DisorganizationLi-Nan Xu0Ying-Ying Sun1Yan-Feng Tan2Xin-Yue Zhou3Tian-Chao Xiang4Ye Fang5Fei Li6Qian Shen7Hong Xu8Jia Rao9Department of Nephrology, Children’s Hospital of Fudan University, National Pediatric Medical Center of China, Shanghai 201100, ChinaDepartment of Nephrology, Children’s Hospital of Fudan University, National Pediatric Medical Center of China, Shanghai 201100, ChinaShanghai Key Lab of Birth Defect, Children’s Hospital of Fudan University, Shanghai 201100, ChinaDepartment of Nephrology, Children’s Hospital of Fudan University, National Pediatric Medical Center of China, Shanghai 201100, ChinaShanghai Key Lab of Birth Defect, Children’s Hospital of Fudan University, Shanghai 201100, ChinaDepartment of Nephrology, Children’s Hospital of Fudan University, National Pediatric Medical Center of China, Shanghai 201100, ChinaDepartment of Developmental and Behavioral Pediatric & Child Primary Care, Ministry of Education-Shanghai Key Laboratory of Children’s Environmental Health, Xin Hua Hospital Affiliated Shanghai Jiao Tong University School of Medicine, Shanghai 200092, ChinaDepartment of Nephrology, Children’s Hospital of Fudan University, National Pediatric Medical Center of China, Shanghai 201100, ChinaDepartment of Nephrology, Children’s Hospital of Fudan University, National Pediatric Medical Center of China, Shanghai 201100, ChinaShanghai Key Lab of Birth Defect, Children’s Hospital of Fudan University, Shanghai 201100, China<i>SHROOM3</i> encodes an actin-binding protein involved in kidney development and has been associated with chronic kidney disease through genome-wide association studies. However, its regulatory role in proteinuric kidney diseases and its mechanistic contributions to podocyte homeostasis remain poorly defined. Here, we analyzed single-cell transcriptomic datasets and the Nephroseq database to delineate <i>SHROOM3</i> expression patterns in proteinuric kidney diseases. Using podocyte-specific <i>SHROOM3</i> knockout mice and an Adriamycin (ADR)-induced nephropathy mouse model, we demonstrated that glomerular <i>SHROOM3</i>, specifically in podocytes, was upregulated following ADR treatment during the acute injury phase but downregulated in chronic kidney disease. Clinically, the glomerular <i>SHROOM3</i> expression positively correlated with glomerular filtration rates in focal segmental glomerulosclerosis patients. Genetic ablation of <i>SHROOM3</i> in podocytes exacerbated ADR-induced proteinuria, diminished podocyte markers (nephrin, podocin, and WT1), and accelerated glomerulosclerosis. In vitro, <i>SHROOM3</i> deficiency impaired podocyte size and adhesion, concomitant with the downregulation of focal adhesion molecules (talin1, vinculin, and paxillin) and stress fiber regulators (synaptopodin and RhoA), as well as calpain activation and RhoA inactivation. Our findings reveal a critical role for <i>SHROOM3</i> in maintaining podocyte integrity and suggest its therapeutic potential in mitigating proteinuric kidney disease progression.https://www.mdpi.com/2073-4409/14/12/895<i>SHROOM3</i>podocyteADR-induced nephropathy |
| spellingShingle | Li-Nan Xu Ying-Ying Sun Yan-Feng Tan Xin-Yue Zhou Tian-Chao Xiang Ye Fang Fei Li Qian Shen Hong Xu Jia Rao <i>SHROOM3</i> Deficiency Aggravates Adriamycin-Induced Nephropathy Accompanied by Focal Adhesion Disassembly and Stress Fiber Disorganization Cells <i>SHROOM3</i> podocyte ADR-induced nephropathy |
| title | <i>SHROOM3</i> Deficiency Aggravates Adriamycin-Induced Nephropathy Accompanied by Focal Adhesion Disassembly and Stress Fiber Disorganization |
| title_full | <i>SHROOM3</i> Deficiency Aggravates Adriamycin-Induced Nephropathy Accompanied by Focal Adhesion Disassembly and Stress Fiber Disorganization |
| title_fullStr | <i>SHROOM3</i> Deficiency Aggravates Adriamycin-Induced Nephropathy Accompanied by Focal Adhesion Disassembly and Stress Fiber Disorganization |
| title_full_unstemmed | <i>SHROOM3</i> Deficiency Aggravates Adriamycin-Induced Nephropathy Accompanied by Focal Adhesion Disassembly and Stress Fiber Disorganization |
| title_short | <i>SHROOM3</i> Deficiency Aggravates Adriamycin-Induced Nephropathy Accompanied by Focal Adhesion Disassembly and Stress Fiber Disorganization |
| title_sort | i shroom3 i deficiency aggravates adriamycin induced nephropathy accompanied by focal adhesion disassembly and stress fiber disorganization |
| topic | <i>SHROOM3</i> podocyte ADR-induced nephropathy |
| url | https://www.mdpi.com/2073-4409/14/12/895 |
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