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. 2023 Dec 6:11:e16499.
doi: 10.7717/peerj.16499. eCollection 2023.

Proximal tubule cells in blood and urine as potential biomarkers for kidney disease biopsy

Minwa Lin #  1 , Yingxue Zhong #  2 , Dan Zhou  3 , Baozhang Guan  2 , Bo Hu  2 , Panpan Wang  4 , Fanna Liu  2
Affiliations

Proximal tubule cells in blood and urine as potential biomarkers for kidney disease biopsy

Minwa Lin et al. PeerJ. .

Abstract

Early diagnosis and treatment are crucial for managing kidney disease, yet there remains a need to further explore pathological mechanisms and develop minimally invasive diagnostic methods. In this study, we employed single-cell RNA sequencing (scRNA-seq) to assess the cellular heterogeneity of kidney diseases. We analyzed gene expression profiles from renal tissue, peripheral blood mononuclear cells (PBMCs), and urine of four patients with nephritis. Our findings identified 12 distinct cell subsets in renal tissues and leukocytes. These subsets encompassed fibroblast cells, mesangial cells, epithelial cells, proximal tubule cells (PTCs), and six immune cell types: CD8+ T cells, macrophages, natural killer cells, dendritic cells, B cells, and neutrophils. Interestingly, PTCs were present in both PBMCs and urine samples but absent in healthy blood samples. Furthermore, several populations of fibroblast cells, mesangial cells, and PTCs exhibited pro-inflammatory or pro-apoptotic behaviors. Our gene expression analysis highlighted the critical role of inflammatory PTCs and fibroblasts in nephritis development and progression. These cells showed high expression of pro-inflammatory genes, which could have chemotactic and activating effect on neutrophils. This was substantiated by the widespread in these cells. Notably, the gene expression profiles of inflammatory PTCs in PBMCs, urine, and kidney tissues had high similarity. This suggests that PTCs in urine and PBMCs hold significant potential as alternative markers to invasive kidney biopsies.

Keywords: Cell exfoliation; Inflammatory proximal tubule cells; Nephritis; Neutropil; Single-cell sequencing.

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Conflict of interest statement

The authors declare there are no competing interests.

Figures

Figure 1
Figure 1. Pathological changes and global renal cell atlas of renal tissues.
(A) Hematein-eosin staining of renal tissues collected from the four patients. Scale bar = 20 µM. (B) t-Distributed stochastic neighbor embedding showing the 12 distinct cell types. Cluster 0, fibrotic fibroblast cells. Cluster 1, preapoptotic mesangial cells. Cluster 2, CD8 + T cells. Cluster 3, epithelial cells (descending and ascending limbs). Cluster 4, inflammatory proximal tubule cells. Cluster 5, proximal tubule cells. Cluster 6, macrophages. Cluster 7, natural killer cells. Cluster 8, fibroblasts. Cluster 9, dendritic cells. Cluster 10, B cells. Cluster 11, neutrophils. (C) Distribution of cells from the four samples in the 12 clusters. (D) Distribution of cells from the four samples in the 12 clusters.
Figure 2
Figure 2. Violin plots showing the expression levels of representative marker genes of Cluster 0 across the 12 clusters.
Figure 3
Figure 3. Violin plots showing the expression of representative marker genes of Cluster 1 across the 12 clusters.
Figure 4
Figure 4. Classification of proximal tubule cells (PTCs) and gene ontology (GO) analysis of differentially expressed genes (DEGs) in blood and urine PTCs.
(A) t-Distributed stochastic neighbor embedding clustering of blood cells from the four patients. (B) t-Distributed stochastic neighbor embedding clustering of blood cells from the five healthy control subjects. (C) Top 20 DEGs of PTCs in peripheral blood mononuclear cells (PBMCs) and tissues. (D) Top 20 significant enriched pathways of DEGs in PTCs between PBMCs and tissues. (E) t-Distributed stochastic neighbor embedding clustering of urine cells from the four patients. (F) Distribution of urine cells from the four samples in the seven clusters. (G) Top 20 DEGs of PTCs in PBMCs and urine. (H) Top 20 significant enriched GO pathways of DEGs in PTCs between PBMCs and urine.
Figure 5
Figure 5. Upregulated inflammation in the proximal tubule cells (PTCs) and neutrophils of the kidney.
(A) Top 20 differentially expressed genes (DEGs) of PTCs and Inflam-PTCs. (B) Gene Ontology (GO) analysis of DEGs of PTCs and Inflam-PTCs. (C) Top 10 significantly enriched pathways of DEGs. (D) Top 20 DEGs in neutrophils derived from the tissues and peripheral blood mononuclear cells (PBMCs). (E) GO analysis of DEGs of neutrophils derived from the tissue and PBMCs.
Figure 6
Figure 6. Potential developmental trajectories of proximal tubule cells (PTCs) based on their expression of marker genes.
(A) Top 20 markers of PTCs. (B) Branched structure of the CD8+ T-cell developmental trajectory in each patient. (C) Distribution of PTCs in each statue.
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Grants and funding

This work was funded by the GuangDong Basic and Applied Basic Research Foundation (No. 2022A1515012641). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.