Cell-type-specific molecular characterization of cells from circulation and kidney in IgA nephropathy with nephrotic syndrome

Qilin Chen; Huimin Jiang; Rong Ding; Jinjie Zhong; Longfei Li; Junli Wan; Xiaoqian Feng; Liping Peng; Xia Yang; Han Chen; Anshuo Wang; Jia Jiao; Qin Yang; Xuelan Chen; Xiaoqin Li; Lin Shi; Gaofu Zhang; Mo Wang; Haiping Yang; Qiu Li

doi:10.3389/fimmu.2023.1231937

Cell-type-specific molecular characterization of cells from circulation and kidney in IgA nephropathy with nephrotic syndrome

Front Immunol. 2023 Oct 16:14:1231937. doi: 10.3389/fimmu.2023.1231937. eCollection 2023.

Authors

Qilin Chen^{1

2

3}, Huimin Jiang^{1

2

3}, Rong Ding⁴, Jinjie Zhong^{1

2

3}, Longfei Li⁴, Junli Wan^{1

2}, Xiaoqian Feng^{1

2

3}, Liping Peng^{1

2

3}, Xia Yang^{1

2

3}, Han Chen^{1

2}, Anshuo Wang^{1

2}, Jia Jiao^{1

2}, Qin Yang^{1

2}, Xuelan Chen^{1

2}, Xiaoqin Li^{1

2}, Lin Shi^{1

2}, Gaofu Zhang^{1

2}, Mo Wang^{1

2}, Haiping Yang^{1

2}, Qiu Li^{1

2

3}

Affiliations

¹ Department of Nephrology, Children's Hospital of Chongqing Medical University, Chongqing, China.
² National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China.
³ Chongqing Key Laboratory of Pediatrics, Chongqing, China.
⁴ Nanjing Jiangbei New Area Biopharmaceutical Public Service Platform Co. Ltd, Nanjing, Jiangsu, China.

Abstract

Nephrotic syndrome (NS) is a relatively rare and serious presentation of IgA nephropathy (IgAN) (NS-IgAN). Previous research has suggested that the pathogenesis of NS-IgAN may involve circulating immune imbalance and kidney injury; however, this has yet to be fully elucidated. To investigate the cellular and molecular status of NS-IgAN, we performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) and kidney cells from pediatric patients diagnosed with NS-IgAN by renal biopsy. Consistently, the proportion of intermediate monocytes (IMs) in NS-IgAN patients was higher than in healthy controls. Furthermore, flow cytometry confirmed that IMs were significantly increased in pediatric patients with NS. The characteristic expression of VSIG4 and MHC class II molecules and an increase in oxidative phosphorylation may be important features of IMs in NS-IgAN. Notably, we found that the expression level of CCR2 was significantly increased in the CMs, IMs, and NCMs of patients with NS-IgAN. This may be related to kidney injury. Regulatory T cells (Tregs) are classified into two subsets of cells: Treg1 (CCR7 ^high, TCF7 ^high, and HLA-DR ^low) and Treg2 (CCR7 ^low, TCF7 ^low, and HLA-DR ^high). We found that the levels of Treg2 cells expressed significant levels of CCR4 and GATA3, which may be related to the recovery of kidney injury. The state of NS in patients was closely related to podocyte injury. The expression levels of CCL2, PRSS23, and genes related to epithelial-mesenchymal transition were significantly increased in podocytes from NS-IgAN patients. These represent key features of podocyte injury. Our analysis suggests that PTGDS is significantly downregulated following injury and may represent a new marker for podocytes. In this study, we systematically analyzed molecular events in the circulatory system and kidney tissue of pediatric patients with NS-IgAN, which provides new insights for targeted therapy in the future.

Keywords: IgA nephropathy; nephrotic syndrome; peripheral blood mononuclear cells; podocyte; single-cell RNA sequencing.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Child
Glomerulonephritis, IGA* / pathology
HLA-DR Antigens
Humans
Kidney / pathology
Leukocytes, Mononuclear / metabolism
Nephrotic Syndrome* / etiology
Receptors, CCR7

Substances

Receptors, CCR7
HLA-DR Antigens

Grants and funding

This work was supported by the National Key R&D Program of China (Grant No. 2022YFC2705101), the Chongqing Science and Health Joint Medical Research Project (Grant No. 2023GGXM001), the Program for Youth Innovation in Future Medicine, Chongqing Medical University (Grant No. W0098), and through the Special Fund For Postdoctoral Research Projects of Chongqing, China (Grant No. 2011010006602511).