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Abstract: SA-PO961

Early Signaling Events in Renal Compensatory Hypertrophy Revealed via Multi-Omics

Session Information

  • CKD: Pathobiology - II
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2203 CKD (Non-Dialysis): Mechanisms

Authors

  • Kikuchi, Hiroaki, National Institutes of Health, Bethesda, Maryland, United States
  • Yang, Chin-Rang, National Institutes of Health, Bethesda, Maryland, United States
  • Chen, Lihe, National Institutes of Health, Bethesda, Maryland, United States
  • Jung, Hyun Jun, Johns Hopkins University, Baltimore, Maryland, United States
  • Park, Euijung, National Institutes of Health, Bethesda, Maryland, United States
  • Knepper, Mark A., National Institutes of Health, Bethesda, Maryland, United States

Group or Team Name

  • Epithelial Systems Biology Laboratory, Systems Biology Center
Background

Mechanisms involved in compensatory hypertrophy of the kidney remain incompletely understood. New ‘-omic’ methodologies have been recently introduced that have the potential of identifying complex mechanisms. Here we seek to identify the earliest signaling changes in the contralateral kidney after unilateral nephrectomy (UNx) in mice using next-generation sequencing and proteomics techniques.”

Methods

Experiments were done in mice undergoing UNx and sham nephrectomy. At specific time points (24 hours and 72 hours) after surgery, the earliest first portion of the kidney proximal tubule (PT-S1) was manually micro-dissected and utilized for transcriptomic analysis by single-tubule small sample RNA-Seq and single-tubule ATAC seq. Furthermore, quantitative proteomic analysis was carried out using protein mass spectrometry.

Results

Kidney volume was already increased 24 hours after UNx, reaching a plateau at 72 hours. Quantitative morphometry in microdissected proximal tubules showed that significant increases in outer diameter and mean cell volume in proximal tubules, but no clear increase in the cell count per unit length. RNA-Seq in microdissected PT-S1 at 24 hours showed that peroxisome proliferator-activated receptor alpha (PPARA) target genes such as Angptl4, Acot1, Cyp4a14, Fabp1, Hmgcs2 and Mgll were strongly upregulated in PT (confirmed statistically). Motif analysis (HOMER) of sequences corresponding to significantly upregulated single tubule ATAC-seq peaks revealed upregulation of binding site motifs corresponding to PPARA and HNF4A, both lipid-regulated transcription factors. Quantitative protein mass spectrometry revealed increased abundances of PPAR regulated proteins such as HMGCS2, CYP4A14 and ANGPTL4 at 24 hours, consistent with RNA-Seq results.

Conclusion

Conpensatory growth of the kidney is associated with increased proximal tubule cell size, but not cell number. Early stages of compensatory hypertrophy are associated with altered fatty acid and cholesterol metabolism including anabolic pathways required for synthesis of new membranes needed for cell growth.