Metabolic rewiring of the hypertensive kidney

TY - JOUR

T1 - Metabolic rewiring of the hypertensive kidney

AU - Rinschen, Markus M

AU - Palygin, Oleg

AU - Guijas, Carlos

AU - Palermo, Amelia

AU - Palacio-Escat, Nicolas

AU - Domingo-Almenara, Xavier

AU - Montenegro-Burke, Rafael

AU - Saez-Rodriguez, Julio

AU - Staruschenko, Alexander

AU - Siuzdak, Gary

N1 - Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

PY - 2019/12/10

Y1 - 2019/12/10

N2 - 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.

AB - 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.

KW - AMP-Activated Protein Kinases/metabolism

KW - Adenosine Triphosphate/metabolism

KW - Animals

KW - Hypertension, Renal/metabolism

KW - NAD/metabolism

KW - Nephritis/metabolism

KW - Podocytes/metabolism

KW - Rats

KW - Signal Transduction

KW - TOR Serine-Threonine Kinases/metabolism

U2 - 10.1126/scisignal.aax9760

DO - 10.1126/scisignal.aax9760

M3 - SCORING: Journal article

C2 - 31822592

VL - 12

JO - SCI SIGNAL

JF - SCI SIGNAL

SN - 1945-0877

IS - 611

ER -