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

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

JOURNAL=Frontiers in Immunology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1231937

DOI=10.3389/fimmu.2023.1231937

ISSN=1664-3224

ABSTRACT=<p>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 <italic>VSIG4</italic> 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 <italic>CCR2</italic> 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 (<italic>CCR7</italic><sup>high</sup>, <italic>TCF7</italic><sup>high</sup>, and <italic>HLA-DR</italic><sup>low</sup>) and Treg2 (<italic>CCR7</italic><sup>low</sup>, <italic>TCF7</italic><sup>low</sup>, and <italic>HLA-DR</italic><sup>high</sup>). We found that the levels of Treg2 cells expressed significant levels of <italic>CCR4</italic> and <italic>GATA3</italic>, 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 <italic>CCL2</italic>, <italic>PRSS23</italic>, 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 <italic>PTGDS</italic> 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.</p>