Acute kidney injury through a metabolic lens: pathological reprogramming mechanisms and clinical translation potential

Abstract

Acute kidney injury (AKI) represents a clinical syndrome with a bleak short-term prognosis, posing a high risk for the development of chronic kidney diseases and end-stage kidney disease. The underlying mechanisms of AKI are still not fully understood, and effective intervention strategies remain elusive. Enormous energy is required to meet the functional activity in hypermetabolic tubular epithelial cells (TECs), the most vulnerable cell types during AKI. Recent evidence has shed light on the reprogramming of metabolic pathways and the shift in energy substrates under pathological conditions. The reprogrammed metabolic pathway initially serves to compensate for energy shortages and supply substrates for cell repair during the early stages of AKI. However, sustained metabolic dysregulation tend to become detrimental for tubular repair and regeneration. Intriguingly, dynamic alterations in specific metabolites extend beyond their conventional roles as metabolic byproducts, actively participating in pathophysiology through multifaceted regulatory mechanisms during AKI. As yet, clinical therapy for AKI has not yet incorporated the intervention of metabolic disorders, highlighting a vast potential for extensive application. This review aims to summarize recent studies on the role of metabolic pathway reprogramming and metabolites in AKI, while discussing promising therapeutic strategies targeting metabolic reprogramming.

Keywords: BCAAs; acute kidney injury; fatty acid oxidation; glutaminolysis; glycolysis; ketolysis.

FIGURE 1

Metabolic reprogramming of tubular epithelial cells (TECs) during AKI. AKI can be induced by hypoxia, toxins, or urinary obstruction. AKI results in mitochondrial dysfunction and low oxygen availability which impedes the electron transport chain and aerobic respiration. The shift from FAO to glycolysis is widely studied in AKI. In addition, ketolysis, BCAA catabolism, glutaminolysis, polyamine metabolism and their metabolites play different roles in AKI. Red and blue fonts and arrows mean up- and downregulated pathways and metabolites in AKI, black fonts and arrows mean unidentified pathways and metabolites in previous studies. BCAAs, branched-chain amino acids; Suc-CoA, succinyl coenzyme; acetyl-CoA, acetyl coenzyme; acyl-CoA, acyl coenzyme; TCA, tricarboxylic acid; Gln, glutamine; Glu, glutamate; α-KG, α-ketoglutarate; NAD, nicotinamide adenine dinucleotide; FAD, flavin adenine dinucleotide; NADPH, nicotinamide adenine dinucleotide phosphate; G-6-P, glucose-6-phosphate; PPP, pentose phosphate pathway; FA, fatty acid; FAO, fatty acid oxidation; FAS, fatty acid synthesis; CPT1, carnitine palmitoyl-transferase 1; CPT2, carnitine palmitoyl-transferase 2; Try, tryptophan; QUIN, quinolinic acid; ATP, adenosine triphosphate; ADP, adenosine diphosphate; ETC, electron transport chain; e⁻, electron; GABA, γ-aminobutyric acid; Put, putrescine; Spd, spermidine; Spm, spermine. GSSG, oxidized glutathione; GSH, reduced glutathione; H₂O₂, hydrogen peroxide.

FIGURE 2

Downregulated pathways in TECs during AKI. Fatty acids are transported into the mitochondria for oxidation as acylcarnitines through the activity of carnitine CPT1 and CPT2, then acyl-CoA undergoes stepwise oxidation to Ac-CoA and enters the TCA cycle which coupling with oxidative phosphorylation to produce ATP. This process is shut down during AKI which leads to maladaptive tubule repair. Ketolysis, BCAA catabolism, NAD de novo biosynthesis from tryptophan were suppressed during AKI as well. IDH, Isocitrate dehydrogenase; A-KGDH, α-Ketoglutaric acid dehydrogenase; SCS, Succinyl-CoA synthetase; FH, Fumarase; SDH, Succinic dehydrogenase; MDH, Malate dehydrogenase; CS, Citrate synthase; SCD, Stearoyl-CoA Desaturase.

FIGURE 3

Upregulated pathways in TECs during AKI. Glycolysis, pentose phosphate pathway, hexokinase biosynthesis pathway, glutaminolysis pathway were enhanced during AKI. And their final products or intermediate metabolites played different roles during AKI. HK, hexokinase; G-6-P, glucose‐6‐phosphate; F-6-P, fructose‐6‐phosphate; GFAT, glutamine fructose-6-phosphate amidotransferase; phosphoenolpyruvate (PEP), then PEP is catalyzed by pyruvate kinase M2 (PKM2); fructose-1,6-bisphosphatase 1 (FBP1), phosphoenolpyruvate carboxykinase (PCK1/2), PC, pyruvate carboxylase.