Single cell transcriptomics-based comparison of regenerative repair vs. fibrotic response in chronic kidney disease
Final Report Abstract
The primary goal of this DFG project was to identify distinct cell types, cell-type specific transcriptomes and cell composition changes for both regenerative kidney repair and maladaptive injury response in kidney fibrosis/chronic kidney disease using state-of-the-art single cell transcriptomic analysis methods. As part of the project, we were able to delineate transcriptomic phenotypes of kidney disease along a continuous spectrum ranging from acute injury to chronic maladaptive failure: First, we determined the epigenetic program that generates unique cell types in the kidney from nephron progenitors and that is critical for understanding cell type heterogeneity during tissue homeostasis and injury response, such as early podocyte commitment through sustained Foxl1 expression and renal tubular cell commitment towards proximal (Hfn4a) and distal (Tfap2b) fates. Second, we demonstrated in a folic acid mouse model that metabolism (fatty acid oxidation and oxidative phosphorylation) in proximal tubule cells showed the strongest and most reproducible association with cell differentiation and chronic disease development. Third, in a unilateral ureteral obstruction model we uncovered a subset of kidney tubule cells with a profibrotic phenotype characterized by the expression of cytokines and chemokines (e.g., CXCL1) associated with recruitment of immune cells such as CXCR2+ basophils. Finally, we developed a mouse model of adaptive and fibrotic kidney regeneration by titrating kidney ischemic injury dose and identified a specific maladaptive/profibrotic proximal tubule cluster after severe ischemia. This cell cluster was characterized by proinflammatory and profibrotic cytokines and myeloid cell chemotactic factors. In silico druggability analysis highlighted pyroptosis/ferroptosis as vulnerable pathways in these profibrotic cells amenable to pharmacological intervention. In addition, the project enabled accomplishment of related work on diabetic nephropathy and review articles on single cell sequencing in the kidney as well as establishment of several high-quality open access data repositories that can be interrogated by the community in an interactive fashion.
Publications
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The interdependence of epithelial and endothelial metabolism in kidney health and disease. Sci Signal; 13(635)
Balzer, Michael S. & Susztak, Katalin
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How to get started with single cell- RNA sequencing data analysis. J Am Soc Nephrol.; 32(6)1279-92
Balzer, Michael S.; Ma, Ziyuan; Zhou, Jianfu; Abedini, Amin & Susztak, Katalin
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Kidney toxicity of the BRAF-kinase inhibitor vemurafenib is driven by off-target ferrochelatase inhibition. Kidney Int.; 100(6):1214-26
Bai, Yuntao; Kim, Ji Young; Bisunke, Bijay; Jayne, Laura A.; Silvaroli, Josie A.; Balzer, Michael S.; Gandhi, Megha; Huang, Kevin M.; Sander, Veronika; Prosek, Jason; Cianciolo, Rachel E.; Baker, Sharyn D.; Sparreboom, Alex; Jhaveri, Kenar D.; Susztak, Katalin; Bajwa, Amandeep & Pabla, Navjot Singh
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Single cell regulatory landscape of the mouse kidney highlights cellular differentiation programs and disease targets. Nat Commun.; 12(1):2277
Miao, Zhen; Balzer, Michael S.; Ma, Ziyuan; Liu, Hongbo; Wu, Junnan; Shrestha, Rojesh; Aranyi, Tamas; Kwan, Amy; Kondo, Ayano; Pontoglio, Marco; Kim, Junhyong; Li, Mingyao; Kaestner, Klaus H. & Susztak, Katalin
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Single-cell biology—a Keystone Symposia report. Ann NY Acad Sci.; 1506(1):74-97
Cable, Jennifer; Elowitz, Michael B.; Domingos, Ana I.; Habib, Naomi; Itzkovitz, Shalev; Hamidzada, Homaira; Balzer, Michael S.; Yanai, Itai; Liberali, Prisca; Whited, Jessica; Streets, Aaron; Cai, Long; Stergachis, Andrew B.; Hong, Clarice Kit Yee; Keren, Leeat; Guilliams, Martin; Alon, Uri; Shalek, Alex K.; Hamel, Regan; ... & Romeike, Merrit
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The Nuclear Receptor ESRRA Protects from Kidney Disease by Coupling Metabolism and Differentiation. Cell Metab.; 33(2):379-94
Dhillon, Poonam; Park, Jihwan; Hurtado del Pozo, Carmen; Li, Lingzhi; Doke, Tomohito; Huang, Shizheng; Zhao, Juanjuan; Kang, Hyun Mi; Shrestra, Rojesh; Balzer, Michael S.; Chatterjee, Shatakshee; Prado, Patricia; Han, Seung Yub; Liu, Hongbo; Sheng, Xin; Dierickx, Pieterjan; Batmanov, Kirill; Romero, Juan P.; Prósper, Felipe; ... & Susztak, Katalin
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Urinary single-cell profiling captures the cellular diversity of the kidney. J Am Soc Nephrol.; 32(3):614-27
Abedini, Amin; Zhu, Yuan O.; Chatterjee, Shatakshee; Halasz, Gabor; Devalaraja-Narashimha, Kishor; Shrestha, Rojesh; S. Balzer, Michael; Park, Jihwan; Zhou, Tong; Ma, Ziyuan; Sullivan, Katie Marie; Hu, Hailong; Sheng, Xin; Liu, Hongbo; Wei, Yi; Boustany-Kari, Carine M.; Patel, Uptal; Almaani, Salem; Palmer, Matthew; ... & Susztak, Katalin
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How Many Cell Types Are in the Kidney and What Do They Do? Annu Rev Physiol; 84:507-31
Balzer, Michael S.; Rohacs, Tibor & Susztak, Katalin
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Single-cell analysis highlights differences in druggable pathways underlying adaptive or fibrotic kidney regeneration. Nat Commun. 13(1):4018
Balzer, Michael S.; Doke, Tomohito; Yang, Ya-Wen; Aldridge, Daniel L.; Hu, Hailong; Mai, Hung; Mukhi, Dhanunjay; Ma, Ziyuan; Shrestha, Rojesh; Palmer, Matthew B.; Hunter, Christopher A. & Susztak, Katalin
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Single-cell analysis identifies the interaction of altered renal tubules with basophils orchestrating kidney fibrosis. Nat Immunol; 23(6):947-59
Doke, Tomohito; Abedini, Amin; Aldridge, Daniel L.; Yang, Ya-Wen; Park, Jihwan; Hernandez, Christina M.; Balzer, Michael S.; Shrestra, Rojesh; Coppock, Gaia; Rico, Juan M. Inclan; Han, Seung Yub; Kim, Junhyong; Xin, Sheng; Piliponsky, Adrian M.; Angelozzi, Marco; Lefebvre, Veronique; Siracusa, Mark C.; Hunter, Christopher A. & Susztak, Katalin
