Metabolic rewiring of the hypertensive kidney

Research output: Contribution to journalArticle

Authors

  • Markus M. Rinschen
  • Oleg Palygin
  • Carlos Guijas
  • Amelia Palermo
  • Nicolas Palacio-Escat
  • Xavier Domingo-Almenara
  • Rafael Montenegro-Burke
  • Julio Saez-Rodriguez
  • Alexander Staruschenko
  • Gary Siuzdak

External Institution(s)

  • Scripps Research Institute
  • University of Cologne
  • RWTH Aachen University
  • Heidelberg University 

Details

Original languageEnglish (US)
Article numbereaax9760
JournalScience signaling
Volume12
Issue number611
StatusPublished - Dec 10 2019
Peer-reviewedYes

Abstract

Hypertension is a persistent epidemic across the developed world that is closely associated with kidney disease. Here, we applied a metabolomic, phosphoproteomic, and proteomic strategy to analyze the effect of hypertensive insults on kidneys. Our data revealed the metabolic aspects of hypertension-induced glomerular sclerosis, including lipid breakdown at early disease stages and activation of anaplerotic pathways to regenerate energy equivalents to counter stress. For example, branched-chain amino acids and proline, required for collagen synthesis, were depleted in glomeruli at early time points. Furthermore, indicators of metabolic stress were reflected by low amounts of ATP and NADH and an increased abundance of oxidized lipids derived from lipid breakdown. These processes were specific to kidney glomeruli where metabolic signaling occurred through mTOR and AMPK signaling. Quantitative phosphoproteomics combined with computational modeling suggested that these processes controlled key molecules in glomeruli and specifically podocytes, including cytoskeletal components and GTP-binding proteins, which would be expected to compete for decreasing amounts of GTP at early time points. As a result, glomeruli showed increased expression of metabolic enzymes of central carbon metabolism, amino acid degradation, and lipid oxidation, findings observed in previously published studies from other disease models and patients with glomerular damage. Overall, multilayered omics provides an overview of hypertensive kidney damage and suggests that metabolic or dietary interventions could prevent and treat glomerular disease and hypertension-induced nephropathy.

Citation formats

APA

Rinschen, M. M., Palygin, O., Guijas, C., Palermo, A., Palacio-Escat, N., Domingo-Almenara, X., ... Siuzdak, G. (2019). Metabolic rewiring of the hypertensive kidney. Science signaling, 12(611), [eaax9760]. https://doi.org/10.1126/scisignal.aax9760

Harvard

Rinschen, MM, Palygin, O, Guijas, C, Palermo, A, Palacio-Escat, N, Domingo-Almenara, X, Montenegro-Burke, R, Saez-Rodriguez, J, Staruschenko, A & Siuzdak, G 2019, 'Metabolic rewiring of the hypertensive kidney', Science signaling, vol. 12, no. 611, eaax9760. https://doi.org/10.1126/scisignal.aax9760