TY - JOUR
T1 - Single-Nucleus Transcriptional Profiling of Chronic Kidney Disease after Cisplatin Nephrotoxicity
AU - Ma, Zhengwei
AU - Hu, Xiaoru
AU - Ding, Han Fei
AU - Zhang, Ming
AU - Huo, Yuqing
AU - Dong, Zheng
N1 - Funding Information:
Supported in part by the US NIH 5R01DK058831 and 5R01DK087843 (Z.D.) and the US Department of Veterans Affairs I01 BX000319 (Z.D.). Z.D. is a recipient of the US Department of Veterans Affairs Senior Research Career Scientist award 1TK6BX005236 .
Publisher Copyright:
© 2022 American Society for Investigative Pathology
PY - 2022/4
Y1 - 2022/4
N2 - Cisplatin induces both acute and chronic nephrotoxicity during chemotherapy in patients with cancer. Presented here is the first study of single-nucleus RNA sequencing (snRNA-seq) of cisplatin-induced nephrotoxicity. Repeated low-dose cisplatin treatment (RLDC) led to decreases in renal function and kidney weight in mice at 9 weeks. The kidneys of these mice showed tubular degeneration and dilation. snRNA-seq identified 16 cell types and 17 cell clusters in these kidneys. Cluster-by-cluster comparison demonstrated cell type–specific changes in gene expression and identified a unique proximal tubule (PT) injury/repair cluster that co-expressed the injury marker kidney injury molecule-1 (Kim1) and the proliferation marker Ki-67. Compared with control, post-RLDC kidneys had 424 differentially expressed genes in PT cells, including tubular transporters and cytochrome P450 enzymes involved in lipid metabolism. snRNA-seq also revealed transcriptional changes in potential PT injury markers (Krt222, Eda2r, Ltbp2, and Masp1) and repair marker (Bex4). RLDC induced inflammation and proinflammatory cytokines (RelB, TNF-α, Il7, Ccl2, and Cxcl2) and the expression of fibrosis markers (fibronectin, collagen I, connective tissue growth factor, vimentin, and α-smooth muscle actin). Together, these results provide new insights into RLDC-induced transcriptional changes at the single-cell level that may contribute to the development of chronic kidney problems in patients with cancer after cisplatin chemotherapy.
AB - Cisplatin induces both acute and chronic nephrotoxicity during chemotherapy in patients with cancer. Presented here is the first study of single-nucleus RNA sequencing (snRNA-seq) of cisplatin-induced nephrotoxicity. Repeated low-dose cisplatin treatment (RLDC) led to decreases in renal function and kidney weight in mice at 9 weeks. The kidneys of these mice showed tubular degeneration and dilation. snRNA-seq identified 16 cell types and 17 cell clusters in these kidneys. Cluster-by-cluster comparison demonstrated cell type–specific changes in gene expression and identified a unique proximal tubule (PT) injury/repair cluster that co-expressed the injury marker kidney injury molecule-1 (Kim1) and the proliferation marker Ki-67. Compared with control, post-RLDC kidneys had 424 differentially expressed genes in PT cells, including tubular transporters and cytochrome P450 enzymes involved in lipid metabolism. snRNA-seq also revealed transcriptional changes in potential PT injury markers (Krt222, Eda2r, Ltbp2, and Masp1) and repair marker (Bex4). RLDC induced inflammation and proinflammatory cytokines (RelB, TNF-α, Il7, Ccl2, and Cxcl2) and the expression of fibrosis markers (fibronectin, collagen I, connective tissue growth factor, vimentin, and α-smooth muscle actin). Together, these results provide new insights into RLDC-induced transcriptional changes at the single-cell level that may contribute to the development of chronic kidney problems in patients with cancer after cisplatin chemotherapy.
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U2 - 10.1016/j.ajpath.2021.12.012
DO - 10.1016/j.ajpath.2021.12.012
M3 - Article
C2 - 35092726
AN - SCOPUS:85126426813
SN - 0002-9440
VL - 192
SP - 613
EP - 628
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 4
ER -
