Version 1
: Received: 9 May 2024 / Approved: 10 May 2024 / Online: 10 May 2024 (10:45:30 CEST)
How to cite:
Song, X.; Pickel, L.; Song, H.-K.; Scholey, J.; Pei, Y. Reprogramming of Energy Metabolism in Human PKD1 Polycystic Kidney Disease: A Systems Biology Analysis. Preprints2024, 2024050678. https://doi.org/10.20944/preprints202405.0678.v1
Song, X.; Pickel, L.; Song, H.-K.; Scholey, J.; Pei, Y. Reprogramming of Energy Metabolism in Human PKD1 Polycystic Kidney Disease: A Systems Biology Analysis. Preprints 2024, 2024050678. https://doi.org/10.20944/preprints202405.0678.v1
Song, X.; Pickel, L.; Song, H.-K.; Scholey, J.; Pei, Y. Reprogramming of Energy Metabolism in Human PKD1 Polycystic Kidney Disease: A Systems Biology Analysis. Preprints2024, 2024050678. https://doi.org/10.20944/preprints202405.0678.v1
APA Style
Song, X., Pickel, L., Song, H. K., Scholey, J., & Pei, Y. (2024). Reprogramming of Energy Metabolism in Human <em>PKD1</em> Polycystic Kidney Disease: A Systems Biology Analysis. Preprints. https://doi.org/10.20944/preprints202405.0678.v1
Chicago/Turabian Style
Song, X., James Scholey and York Pei. 2024 "Reprogramming of Energy Metabolism in Human <em>PKD1</em> Polycystic Kidney Disease: A Systems Biology Analysis" Preprints. https://doi.org/10.20944/preprints202405.0678.v1
Abstract
(1) Background: Multiple alterations of cellular metabolism have been documented in experimental studies of autosomal dominant polycystic kidney disease (ADPKD) and are thought to contribute to its pathogenesis. (2) Methods: To elucidate the molecular pathways and transcriptional regulators associated with the metabolic changes of renal cysts in ADPKD, we compared global gene expression data from human PKD1 renal cysts, minimally cystic tissues (MCT) from the same patients, and healthy human kidney cortical tissue samples. (3) Results: We found PKD1 renal cysts displayed the Warburg effect with gene pathway changes favoring increased cellular glucose uptake and lactate production, instead of pyruvate oxidation. Additionally, mitochondrial energy metabolism was globally depressed, associated with downregulation of gene pathways related to fatty acid oxidation (FAO), branched-chain amino acid (BCAA) degradation, the Krebs cycle, and oxidative phosphorylation (OXPHOS) in renal cysts. Activation of mTORC1 and its two target proto-oncogenes, HIF-1α and MYC, was predicted to drive the expression of multiple genes involved in the observed metabolic reprogramming (e.g., GLUT3, HK1/HK2, ALDOA, ENO2, PKM, LDHA/LDHB, MCT4, PDHA1, PDK1/3, MPC1/2, CPT2, BCAT1, NAMPT); indeed, their predicted expression patterns were confirmed by our data. Conversely, we found AMPK inhibition was predicted in renal cysts. AMPK inhibition was associated with decreased expression of PGC-1α, a transcriptional coactivator for transcription factors PPARα, ERRα, and ERRγ, all of which play a critical role in regulating oxidative metabolism and mitochondrial biogenesis. (4) Conclusions: These data provide a comprehensive map of metabolic pathway reprogramming in ADPKD and highlight nodes of regulation that may serve as targets for therapeutic intervention.
Keywords
ADPKD; renal cysts; global gene profiling; metabolic reprogramming
Subject
Medicine and Pharmacology, Urology and Nephrology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
