Integrated genomic, transcriptomic and metabolomic analysis reveals MDH2 mutation-induced metabolic disorder in recurrent focal segmental glomerulosclerosis
Focal segmental glomerulosclerosis (FSGS) has an over 30% risk of recurrence after kidney transplantation (Ktx) and is associated with an extremely high risk of graft loss. However, mechanisms remain largely unclear. Thus, this study identifies novel genes related to the recurrence of FSGS (rFSGS)....
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.962986/full |
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| author | Qixia Shen Qixia Shen Qixia Shen Qixia Shen Lisha Teng Lisha Teng Lisha Teng Lisha Teng Yucheng Wang Yucheng Wang Yucheng Wang Yucheng Wang Luying Guo Luying Guo Luying Guo Luying Guo Feng Xu Hongfeng Huang Hongfeng Huang Hongfeng Huang Hongfeng Huang Wenqing Xie Wenqing Xie Wenqing Xie Wenqing Xie Qin Zhou Qin Zhou Qin Zhou Qin Zhou Ying Chen Ying Chen Ying Chen Ying Chen Junwen Wang Youying Mao Jianghua Chen Jianghua Chen Jianghua Chen Jianghua Chen Hong Jiang Hong Jiang Hong Jiang Hong Jiang |
| author_facet | Qixia Shen Qixia Shen Qixia Shen Qixia Shen Lisha Teng Lisha Teng Lisha Teng Lisha Teng Yucheng Wang Yucheng Wang Yucheng Wang Yucheng Wang Luying Guo Luying Guo Luying Guo Luying Guo Feng Xu Hongfeng Huang Hongfeng Huang Hongfeng Huang Hongfeng Huang Wenqing Xie Wenqing Xie Wenqing Xie Wenqing Xie Qin Zhou Qin Zhou Qin Zhou Qin Zhou Ying Chen Ying Chen Ying Chen Ying Chen Junwen Wang Youying Mao Jianghua Chen Jianghua Chen Jianghua Chen Jianghua Chen Hong Jiang Hong Jiang Hong Jiang Hong Jiang |
| author_sort | Qixia Shen |
| collection | DOAJ |
| description | Focal segmental glomerulosclerosis (FSGS) has an over 30% risk of recurrence after kidney transplantation (Ktx) and is associated with an extremely high risk of graft loss. However, mechanisms remain largely unclear. Thus, this study identifies novel genes related to the recurrence of FSGS (rFSGS). Whole genome-wide sequencing and next-generation RNA sequencing were used to identify the candidate mutant genes associated with rFSGS in peripheral blood mononuclear cells (PBMCs) from patients with biopsy-confirmed rFSGS after KTx. To confirm the functional role of the identified gene with the MDH2 c.26C >T mutation, a homozygous MDH2 c.26C >T mutation in HMy2.CIR cell line was induced by CRISPR/Cas9 and co-cultured with podocytes, mesangial cells, or HK2 cells, respectively, to detect the potential pathogenicity of the c.26C >T variant in MDH2. A total of 32 nonsynonymous single nucleotide polymorphisms (SNPs) and 610 differentially expressed genes (DEGs) related to rFSGS were identified. DEGs are mainly enriched in the immune and metabolomic-related pathways. A variant in MDH2, c.26C >T, was found in all patients with rFSGS, which was also accompanied by lower levels of mRNA expression in PBMCs from relapsed patients compared with patients with remission after KTx. Functionally, co-cultures of HMy2.CIR cells overexpressing the mutant MDH2 significantly inhibited the expression of synaptopodin, podocin, and F-actin by podocytes compared with those co-cultured with WT HMy2.CIR cells or podocytes alone. We identified that MDH2 is a novel rFSGS susceptibility gene in patients with recurrence of FSGS after KTx. Mutation of the MDH2 c.26C >T variant may contribute to progressive podocyte injury in rFSGS patients. |
| first_indexed | 2024-04-11T21:14:06Z |
| format | Article |
| id | doaj.art-b968966104334287a4f773f25594c4b4 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-11T21:14:06Z |
| publishDate | 2022-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-b968966104334287a4f773f25594c4b42022-12-22T04:02:54ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-09-011310.3389/fimmu.2022.962986962986Integrated genomic, transcriptomic and metabolomic analysis reveals MDH2 mutation-induced metabolic disorder in recurrent focal segmental glomerulosclerosisQixia Shen0Qixia Shen1Qixia Shen2Qixia Shen3Lisha Teng4Lisha Teng5Lisha Teng6Lisha Teng7Yucheng Wang8Yucheng Wang9Yucheng Wang10Yucheng Wang11Luying Guo12Luying Guo13Luying Guo14Luying Guo15Feng Xu16Hongfeng Huang17Hongfeng Huang18Hongfeng Huang19Hongfeng Huang20Wenqing Xie21Wenqing Xie22Wenqing Xie23Wenqing Xie24Qin Zhou25Qin Zhou26Qin Zhou27Qin Zhou28Ying Chen29Ying Chen30Ying Chen31Ying Chen32Junwen Wang33Youying Mao34Jianghua Chen35Jianghua Chen36Jianghua Chen37Jianghua Chen38Hong Jiang39Hong Jiang40Hong Jiang41Hong Jiang42Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, ChinaKey Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, ChinaZhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, ChinaInstitute of Nephrology, Zhejiang University, Hangzhou, ChinaKidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, ChinaKey Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, ChinaZhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, ChinaInstitute of Nephrology, Zhejiang University, Hangzhou, ChinaKidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, ChinaKey Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, ChinaZhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, ChinaInstitute of Nephrology, Zhejiang University, Hangzhou, ChinaKidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, ChinaKey Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, ChinaZhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, ChinaInstitute of Nephrology, Zhejiang University, Hangzhou, ChinaThe Centre for Heart and Lung Innovation, The University of British Columbia, Vancouver, BC, CanadaKidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, ChinaKey Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, ChinaZhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, ChinaInstitute of Nephrology, Zhejiang University, Hangzhou, ChinaKidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, ChinaKey Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, ChinaZhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, ChinaInstitute of Nephrology, Zhejiang University, Hangzhou, ChinaKidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, ChinaKey Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, ChinaZhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, ChinaInstitute of Nephrology, Zhejiang University, Hangzhou, ChinaKidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, ChinaKey Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, ChinaZhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, ChinaInstitute of Nephrology, Zhejiang University, Hangzhou, ChinaDepartment of Health Sciences Research and Center for Individualized Medicine, Mayo Clinic, Scottsdale, AZ, United StatesDapartment of Nephrology, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiaotong University, Shanghai, ChinaKidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, ChinaKey Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, ChinaZhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, ChinaInstitute of Nephrology, Zhejiang University, Hangzhou, ChinaKidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, ChinaKey Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, ChinaZhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, ChinaInstitute of Nephrology, Zhejiang University, Hangzhou, ChinaFocal segmental glomerulosclerosis (FSGS) has an over 30% risk of recurrence after kidney transplantation (Ktx) and is associated with an extremely high risk of graft loss. However, mechanisms remain largely unclear. Thus, this study identifies novel genes related to the recurrence of FSGS (rFSGS). Whole genome-wide sequencing and next-generation RNA sequencing were used to identify the candidate mutant genes associated with rFSGS in peripheral blood mononuclear cells (PBMCs) from patients with biopsy-confirmed rFSGS after KTx. To confirm the functional role of the identified gene with the MDH2 c.26C >T mutation, a homozygous MDH2 c.26C >T mutation in HMy2.CIR cell line was induced by CRISPR/Cas9 and co-cultured with podocytes, mesangial cells, or HK2 cells, respectively, to detect the potential pathogenicity of the c.26C >T variant in MDH2. A total of 32 nonsynonymous single nucleotide polymorphisms (SNPs) and 610 differentially expressed genes (DEGs) related to rFSGS were identified. DEGs are mainly enriched in the immune and metabolomic-related pathways. A variant in MDH2, c.26C >T, was found in all patients with rFSGS, which was also accompanied by lower levels of mRNA expression in PBMCs from relapsed patients compared with patients with remission after KTx. Functionally, co-cultures of HMy2.CIR cells overexpressing the mutant MDH2 significantly inhibited the expression of synaptopodin, podocin, and F-actin by podocytes compared with those co-cultured with WT HMy2.CIR cells or podocytes alone. We identified that MDH2 is a novel rFSGS susceptibility gene in patients with recurrence of FSGS after KTx. Mutation of the MDH2 c.26C >T variant may contribute to progressive podocyte injury in rFSGS patients.https://www.frontiersin.org/articles/10.3389/fimmu.2022.962986/fullrecurrent focal segmental glomerulosclerosiskidney transplantationwhole genome sequencingnext-generation RNA sequencingMDH2 |
| spellingShingle | Qixia Shen Qixia Shen Qixia Shen Qixia Shen Lisha Teng Lisha Teng Lisha Teng Lisha Teng Yucheng Wang Yucheng Wang Yucheng Wang Yucheng Wang Luying Guo Luying Guo Luying Guo Luying Guo Feng Xu Hongfeng Huang Hongfeng Huang Hongfeng Huang Hongfeng Huang Wenqing Xie Wenqing Xie Wenqing Xie Wenqing Xie Qin Zhou Qin Zhou Qin Zhou Qin Zhou Ying Chen Ying Chen Ying Chen Ying Chen Junwen Wang Youying Mao Jianghua Chen Jianghua Chen Jianghua Chen Jianghua Chen Hong Jiang Hong Jiang Hong Jiang Hong Jiang Integrated genomic, transcriptomic and metabolomic analysis reveals MDH2 mutation-induced metabolic disorder in recurrent focal segmental glomerulosclerosis Frontiers in Immunology recurrent focal segmental glomerulosclerosis kidney transplantation whole genome sequencing next-generation RNA sequencing MDH2 |
| title | Integrated genomic, transcriptomic and metabolomic analysis reveals MDH2 mutation-induced metabolic disorder in recurrent focal segmental glomerulosclerosis |
| title_full | Integrated genomic, transcriptomic and metabolomic analysis reveals MDH2 mutation-induced metabolic disorder in recurrent focal segmental glomerulosclerosis |
| title_fullStr | Integrated genomic, transcriptomic and metabolomic analysis reveals MDH2 mutation-induced metabolic disorder in recurrent focal segmental glomerulosclerosis |
| title_full_unstemmed | Integrated genomic, transcriptomic and metabolomic analysis reveals MDH2 mutation-induced metabolic disorder in recurrent focal segmental glomerulosclerosis |
| title_short | Integrated genomic, transcriptomic and metabolomic analysis reveals MDH2 mutation-induced metabolic disorder in recurrent focal segmental glomerulosclerosis |
| title_sort | integrated genomic transcriptomic and metabolomic analysis reveals mdh2 mutation induced metabolic disorder in recurrent focal segmental glomerulosclerosis |
| topic | recurrent focal segmental glomerulosclerosis kidney transplantation whole genome sequencing next-generation RNA sequencing MDH2 |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.962986/full |
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