Single-Cell Profiling Reveals Transcriptional Signatures and Cell-Cell Crosstalk in Anti-PLA2R Positive Idiopathic Membranous Nephropathy Patients

Abstract

Idiopathic membranous nephropathy (IMN) is an organ-specific autoimmune disease of the kidney glomerulus. It may gradually progress to end-stage renal disease (ESRD) characterized by increased proteinuria, which leads to serious consequences. Although substantial advances have been made in the understanding of the molecular bases of IMN in the last 10 years, certain questions remain largely unanswered. To define the transcriptomic landscape at single-cell resolution, we analyzed kidney samples from 6 patients with anti-PLA2R positive IMN and 2 healthy control subjects using single-cell RNA sequencing. We then identified distinct cell clusters through unsupervised clustering analysis of kidney specimens. Identification of the differentially expressed genes (DEGs) and enrichment analysis as well as the interaction between cells were also performed. Based on transcriptional expression patterns, we identified all previously described cell types in the kidney. The DEGs in most kidney parenchymal cells were primarily enriched in genes involved in the regulation of inflammation and immune response including IL-17 signaling, TNF signaling, NOD-like receptor signaling, and MAPK signaling. Moreover, cell-cell crosstalk highlighted the extensive communication of mesangial cells, which infers great importance in IMN. IMN with massive proteinuria displayed elevated expression of genes participating in inflammatory signaling pathways that may be involved in the pathogenesis of the progression of IMN. Overall, we applied single-cell RNA sequencing to IMN to uncover intercellular interactions, elucidate key pathways underlying the pathogenesis, and identify novel therapeutic targets of anti-PLA2R positive IMN.

Non-diabetic urine glucose in idiopathic membranous nephropathy

“…Furthermore, the frequency of glycosuria was only 6% in glomerulonephritis [ 17 ]. Tubular injury and the crosstalk between tubular cells and other cells are important processes in the progression of chronic kidney disease [ 18 , 19 ]. Most AKI manifested with the acute renal tubular injury.…”

“…Albumin overload could indeed induce renal tubular injury [ 24 ]. A recent research with single cell sequence also showed that proximal tubular cells had higher TNF signaling pathway, IL-17 signaling pathway, NOD like receptor, and apoptosis expression in massive proteinuria patients than nonmassive proteinuria patients [ 19 ]. Thus, it would be of importance to discriminate the tubular injury when patients had massive proteinuria.…”

Screening of Medications for Idiopathic Membranous Nephropathy Using Glomerular Whole-Genome Sequencing

“…sPLA2-IB can promote podocyte injury by downregulating autophagy by activating the p38 MAPK/mTOR/ULK1 (Ser757) pathway [ 28 ]. Single-cell sequencing analysis of renal tissue from healthy individuals and PLA2R-positive IMN patients revealed that differentially expressed genes in renal parenchymal cells lead to MN through pathways such as MAPK [ 29 ].…”

Intrarenal Single-Cell Sequencing of Hepatitis B Virus Associated Membranous Nephropathy

“…The extracted fresh kidney tissue samples were processed and dissociated into single-cell suspensions using a previously described method (18).…”

“…Since the Humphreys group adopted scRNA-seq in healthy adult kidneys and one kidney transplant biopsy, there have been many advances in singlecell sequencing technology in mapping the human kidney transcriptome (16). Recently, we have taken advantage of this technique to generate renal atlases in IgA nephropathy (17) and membranous nephropathy (18).…”