Frontiers in Immunology (Sep 2022)
Integrated genomic, transcriptomic and metabolomic analysis reveals MDH2 mutation-induced metabolic disorder in recurrent focal segmental glomerulosclerosis
- 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
Affiliations
- Qixia Shen
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Qixia Shen
- Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China
- Qixia Shen
- Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
- Qixia Shen
- Institute of Nephrology, Zhejiang University, Hangzhou, China
- Lisha Teng
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Lisha Teng
- Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China
- Lisha Teng
- Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
- Lisha Teng
- Institute of Nephrology, Zhejiang University, Hangzhou, China
- Yucheng Wang
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Yucheng Wang
- Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China
- Yucheng Wang
- Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
- Yucheng Wang
- Institute of Nephrology, Zhejiang University, Hangzhou, China
- Luying Guo
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Luying Guo
- Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China
- Luying Guo
- Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
- Luying Guo
- Institute of Nephrology, Zhejiang University, Hangzhou, China
- Feng Xu
- The Centre for Heart and Lung Innovation, The University of British Columbia, Vancouver, BC, Canada
- Hongfeng Huang
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Hongfeng Huang
- Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China
- Hongfeng Huang
- Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
- Hongfeng Huang
- Institute of Nephrology, Zhejiang University, Hangzhou, China
- Wenqing Xie
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Wenqing Xie
- Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China
- Wenqing Xie
- Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
- Wenqing Xie
- Institute of Nephrology, Zhejiang University, Hangzhou, China
- Qin Zhou
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Qin Zhou
- Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China
- Qin Zhou
- Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
- Qin Zhou
- Institute of Nephrology, Zhejiang University, Hangzhou, China
- Ying Chen
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Ying Chen
- Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China
- Ying Chen
- Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
- Ying Chen
- Institute of Nephrology, Zhejiang University, Hangzhou, China
- Junwen Wang
- Department of Health Sciences Research and Center for Individualized Medicine, Mayo Clinic, Scottsdale, AZ, United States
- Youying Mao
- Dapartment of Nephrology, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiaotong University, Shanghai, China
- Jianghua Chen
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Jianghua Chen
- Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China
- Jianghua Chen
- Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
- Jianghua Chen
- Institute of Nephrology, Zhejiang University, Hangzhou, China
- Hong Jiang
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Hong Jiang
- Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China
- Hong Jiang
- Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
- Hong Jiang
- Institute of Nephrology, Zhejiang University, Hangzhou, China
- DOI
- https://doi.org/10.3389/fimmu.2022.962986
- Journal volume & issue
-
Vol. 13
Abstract
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.
Keywords
- recurrent focal segmental glomerulosclerosis
- kidney transplantation
- whole genome sequencing
- next-generation RNA sequencing
- MDH2
