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Kidney Week

Abstract: TH-OR72

PPARα, as a Key Determinant of Kidney Size, Revealed by Multi-Omics

Session Information

Category: Transplantation

  • 2101 Transplantation: Basic

Authors

  • Kikuchi, Hiroaki, National Institutes of Health, Bethesda, Maryland, United States
  • Knepper, Mark A., National Institutes of Health, Bethesda, Maryland, United States
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 combined with lipid analysis.

Methods

Experiments were done in mice undergoing UNx and sham nephrectomy. At specific time points (24 hours and 72 hours) after surgery, the earliest 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 and lipid anlaysis were carried out using whole kidney.

Results

Kidney volume was already increased 24 hours after UNx, reaching a plateau at 72 hours. Quantitative morphometry in microdissected proximal tubules showed significant increases in outer diameter and mean cell volume, but no clear increase in the cell count per unit length. Measurements of DNA accessibility (ATAC-seq), transcriptome (RNA-seq) and proteome (quantitative protein mass spectrometry) independently identify patterns of change that are indicative of activation of the lipid-regulated transcription factor, PPARα. Among genes/proteins included as “Lipid Transport”, Cd36, Fabp5, Atp8a1, Atp11c, Gm2a, Gramd1b, Npc2, Apoa2, Apoa4, Atg9a, Cert1, Osbpl9, Slc10a2 and Tex2 were identified as changed in our data integration analysis. Lipid analysis using gas chromatography shows an increased abundance of PPARα ligands in the hypertrophied kidney. Activation of PPARα by fenofibrate administration increases proximal tubule cell size, while genetic deletion of PPARα decreases it.

Conclusion

Compensatory growth of the kidney is associated with increased proximal tubule cell size, but not cell number. PPARα is an important determinant of proximal tubule cell size and is a likely mediator of compensatory proximal tubule hypertrophy. 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.

Funding

  • Other NIH Support