Kidney Week

Abstract: TH-PO563

TRPP2-Dependent Cellular Metabolism and Transcription

Session Information

• Cystic Kidney Diseases - I
  November 02, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Genetic Diseases of the Kidney

• 801 Cystic Kidney Diseases

Authors

• Hofherr, Alexis, Medical Center - University of Freiburg, Freiburg im Breisgau, Germany

Alexis Hofherr,

• Müller, Hannah, Medical Center - University of Freiburg, Freiburg im Breisgau, Germany

Hannah Müller,

• Keller, Sebastian, Medical Center - University of Freiburg, Freiburg im Breisgau, Germany

Sebastian Keller,

• Kottgen, Michael, Medical Center - University of Freiburg, Freiburg im Breisgau, Germany

Michael Kottgen,

Background

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenetic cause of chronic kidney disease, accounting for 7–10 % of patients with end-stage renal disease. ADPKD is caused by loss of function mutations in PKD1 or PKD2. The gene products of PKD1 and PKD2, Polycystin-1 (PC1) and Transient Receptor Potential ion channel Polycystin-2 (TRPP2), form a receptor-ion channel complex of unknown molecular function. In an unbiased forward genetic screen we have previously identified a Short Ca²⁺-binding Mitochondrial metabolite Carrier (SCaMC) as a downstream effector of TRPP2. Here we investigate, whether TRPP2-SCaMC-associated metabolite fluctuations regulate cellular gene expression – translating transient TRPP2 ion channel activity into lasting cellular responses.

Methods

To correlate changes in metabolite levels with cellular gene expression, we performed broad-coverage discovery metabolomics and whole transcriptome shotgun sequencing in differentiated wild-type, PKD2^-/-, and SCaMC^-/- renal epithelial cell lines.

Results

The quantitative measurement of the dynamic multiparametric metabolic response to the pathophysiological loss of TRPP2 and SCaMC identified significantly changed metabolites in both systems. We found that these metabolites are associated with amino acid metabolism including branched chain amino acids (BCAA) in mitochondria. Similarly, the expression of a large number of genes is affected by loss of TRPP2 and SCaMC. We are now correlating concordant changes in cellular metabolism and gene expression to identify novel molecular entities in the polycystin signaling cascade.

Conclusion

We have shown previously that loss of the metabolite carrier SCaMC phenocopies loss of TRPP2 in invertebrate and vertebrate model systems. Emerging evidence suggests that metabolite fluctuations regulate cellular signal transduction. We have tested this hypothesis and discovered a significant number of metabolites and genes indeed regulated by TRPP2 and SCaMC. It is tempting to speculate that concordantly changed molecular entities may provide mechanistic links between the polycystin receptor-ion channel complex and the diverse morphological changes observed in ADPKD.