Fig. 3

Metabolic reprogramming and macrophage polarization. Consistent with their diverse function and energy demands, macrophages adapt their metabolic programming in response to inflammation, injury, repair and fibrosis in CKD. Glycolysis is increased in activated macrophages with an increase in pyruvate production. In M1 macrophages (left side), most pyruvate is not converted to acetyl-CoA due to the blockage of the TCA cycle; rather, there is flux into the pentose phosphate pathway, generating NADPH, nucleotides and amino acids. Accumulation of citrate drives fatty acid synthesis; the accumulation of succinate leads to induction of HIF-1α, promoting expression of inflammatory and glycolytic genes; reverse electron transfer, along with increased NADPH, and HIF-1α, results in ROS overproduction, and activation of NLRP3 inflammasomes. In M2 macrophages (right side), pyruvate is converted into acetyl-CoA and enters the intact TCA cycle, leading to sustained ATP production via oxidative phosphorylation and up-regulation of genes associated with tissue repair; increased levels of fatty acids enter the TCA cycle leading to an increase in β-oxidation and energy production and a decrease in ROS production due to forward electron transfer. In M2 macrophages, arginase-1 drives the production of polyamines and ornithine in contrast to conversion into citrulline and NO in M1 macrophages. F6P, fructose-6-phosphate; G6P, glucose-6-phosphate; GLUT1, glucose transporter 1; NO, nitric oxide; PDC, pyruvate dehydrogenase complex; PPP, Pentose Phosphate Pathway; FAO, Fatty Acid Oxidation