Affiliation:
1. Cincinnati Children's Hospital Medical Center
2. Cytokinetics (United States)
3. University of Cincinnati
Abstract
Abstract
Examining kidney fibrosis is crucial for mechanistic understanding and developing targeted strategies against chronic kidney disease (CKD). Persistent fibroblast activation and tubular epithelial cell (TEC) injury are key CKD contributors. However, cellular and transcriptional landscapes of CKD and specific activated kidney fibroblast clusters remain elusive. Here, we analyzed single cell transcriptomic profiles of two clinically relevant kidney fibrosis models which induced robust kidney parenchymal remodeling. We dissected the molecular and cellular landscapes of kidney stroma and newly identified three distinctive fibroblast clusters with “secretory”, “contractile” and “vascular” transcriptional enrichments. Also, both injuries generated failed repair TECs (frTECs) characterized by decline of mature epithelial markers and elevation of stromal and injury markers. Notably, frTECs shared transcriptional identity with distal nephron segments of the embryonic kidney. Moreover, we identified that both models exhibited robust and previously unrecognized distal spatial pattern of TEC injury, outlined by persistent elevation of renal TEC injury markers including Krt8, while the surviving proximal tubules (PTs) showed restored transcriptional signature. Furthermore, we found that long-term kidney injuries activated a prominent nephrogenic signature, including Sox4 and Hox gene elevation, which prevailed in the distal tubular segments. Our findings might advance understanding of and targeted intervention in fibrotic kidney disease.
Publisher
Research Square Platform LLC
Reference69 articles.
1. Chronic kidney disease;Kalantar-Zadeh K;Lancet,2021
2. Prevalence and Disease Burden of Chronic Kidney Disease;Lv JC;Adv Exp Med Biol,2019
3. System, U. S. R. D. 2021 USRDS Annual Data Report: Epidemiology of kidney disease in the United States. (National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD).
4. Renal Interstitial Platelet-Derived Growth Factor Receptor-beta Cells Support Proximal Tubular Regeneration;Schiessl IM;J Am Soc Nephrol,2018
5. Cellular and molecular mechanisms of kidney fibrosis;Djudjaj S;Mol Aspects Med,2019
Cited by
2 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献