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Abstract: SU-OR13

Renal Proximal Tubule Cell Differentiation and Metabolism Are Coupled by Nuclear Receptors

Session Information

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Dhillon, Poonam, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Park, Jihwan, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Hurtado del Pozo, Carmen, Barcelona Institute of Science and Technology, Barcelona, Spain
  • Li, Lingzhi, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Huang, Shizheng, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Shrestha, Rojesh, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Montserrat, Nuria, Barcelona Institute of Science and Technology, Barcelona, Spain
  • Susztak, Katalin, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Group or Team Name

  • Susztak Lab
Background

Kidney proximal tubule (PT) cells have high mitochondrial density to perform their highly energy demanding function to secrete and reabsorb metabolites and electrolytes. Chronic kidney disease is characterized by tubule epithelial atrophy and dedifferentiation, resulting in a decline in kidney function. In this study, we aimed to define upstream regulators that control PT differentiation.

Methods

We performed scRNA and snATACseq analysis on kidneys of developing and adult mice, kidney organoids, and kidneys from control and folic acid-induced kidney injury model. Bioinformatic methods included dimension reduction, differential expression, cell fraction and cell trajectory analysis. Functional studies included mice and cultured tubule cells with genetic deletion of ESRRA..

Results

Single cell differential expression analysis identified PT cells as the key vulnerable cell type in kidney fibrosis. Cell trajectory analysis showed a sequential differentiation path from precursor to differentiated PT cell state in development and in healthy adult and diseased kidneys. But this differentiation path showed more complexity in fibrosis, such as enhanced cell proliferation and a blockade of terminal differentiation. Pathway analysis indicated fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) were key variable genes along the PT cell differentiation path in the adult, and developing mouse PT cells and organoids. Single cell epigenetics data identified the critical role of nuclear receptors; HNF4A, HNF1B, PPARA, and ESRRA driving the PT cell differentiation program. These transcription factors did not only directly control FAO and OXPHOS but also the expression of PT differentiation genes. Genetic and pharmacological deletion of these transcription factors lead to marked changes in differentiation state of cultured PT cells. Analysis of healthy and disease human kidneys samples and mice with ESRRA deletion showed a defect in FAO, OXPHOS and PT differentiation and was more susceptible for injury, defining a novel role for ESRRA in PT cells and CKD.

Conclusion

The coupling of cell state and metabolism is established by nuclear receptors such as PPARA and ESRRA that not only control cellular metabolism but also the expression of PT cell-specific genes in mice and patient samples.

Funding

  • NIDDK Support