Metabolic rewiring of the hypertensive kidney

Abstract

Hypertension is a persistent epidemic across the developed world that is closely associated with kidney disease. Here, we applied a metabolomics, phosphoproteomics and proteomics strategy to analyze the effect of hypertensive insults on kidneys. Our data established 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. Further, indicators of metabolic stress were reflected by low levels of ATP and NADH and 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 modelling 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 data from other disease models and patients with glomerular damage. Overall, these results suggest that metabolic interventions could be potentially useful in treating hypertension‐induced kidney disease.