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 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.

The Vicious Cycle of Renal Lipotoxicity and Mitochondrial Dysfunction

“…In a rat model of hypertension and proteinuria, increased metabolic stress was indicated by increased oxidized lipids derived from lipid breakdown in glomeruli at the early stage, causing decreased ATP and NADH levels. The change of metabolic aspects in glomeruli from these mice was associated with the activation of phosphoprotein-dependent signaling such as mTOR and AMPK (Rinschen et al, 2019). Steinberg et al demonstrated that AMPK activity is suppressed by TNFα signaling, resulting in decreased FA β-oxidation and excess lipids in skeletal muscle (Steinberg et al, 2006).…”

Lysine metabolism conveys kidney protection in hypertension

“…We had earlier reported a de cit of lysine metabolites in the kidney cortex in a hypertensive kidney disease model 22 . Based on these ndings, and on a potential bene cial role of lysine in the Framingham cohort 17 and 3 randomized controlled dietary intervention trials [18][19][20] , we hypothesized that administration of lysine can be helpful in a model of hypertensive kidney disease.…”

“…For untargeted metabolomic analysis, we used a UHPLC-MS approach. For fractionation, we used hydrophilic interaction liquid chromatography (HILIC) fractionation and reversed-phase (RP) chromatography as previously described 22 . We used a quadrupole time-of-ight instrument (Impact II, Bruker, Bremen, Germany) coupled to a ultrahigh-performance liquid chromatography (UHPLC) device (Bruker Elute, Bruker, Billerica, MA), or to an Agilent In nity 1290 UHPLC device (Agilent, USA).…”

“…In all cases, a standard curve was recorded and integrated using the mass hunter platform (Agilent). The method for the TCA cycle including transitions was previously published 22 . The transitions used for malonyl-Lysine were as follows: 233 -> 84; 233 -> 129.09, 233 -> 147.10 (for non-labeled malonyl-Lysine) and 239 -> 89, 239 -> 134, 239 -> 153 for 13C6 labeled malonyl-Lysine).…”

“…LC-MS/MS analysis for metabolomics was performed as previously described 22 . Data was annotated with in-source fragments and adducts.…”