Regulation of pericyte metabolic reprogramming restricts the AKI to CKD transition

by Selleckchem | Nov 04 2023

Background and aims: Acute kidney injury (AKI) is associated with high morbidity and mortality and is recognized as a long-term risk factor for progression to chronic kidney disease (CKD). The AKI to CKD transition is characterized by interstitial fibrosis and the proliferation of collagen-secreting myofibroblasts. Pericytes are the major source of myofibroblasts in kidney fibrosis. However, the underlying mechanism of pericyte-myofibroblast transition (PMT) is still unclear. Here we investigated the role of metabolic reprogramming in PMT.

Methods: Unilateral ischemia/reperfusion-induced AKI to CKD mouse model and TGF-β-treated pericyte-like cells were used to detect the levels of fatty acid oxidation (FAO) and glycolysis, and the critical signaling pathways during PMT under the treatment of drugs regulating metabolic reprogramming.

Results: PMT is characterized by a decrease in FAO and an increase in glycolysis. Enhancement of FAO by the peroxisome proliferator-activated receptor gamma coactivator-1α (PGC1α) activator ZLN-005 or suppression of glycolysis by the hexokinase 2 (HK2) inhibitor 2-DG can inhibit PMT, preventing the transition of AKI to CKD. Mechanistically, AMPK modulates various pathways involved in the metabolic switch from glycolysis to FAO. Specifically, the PGC1α-CPT1A pathway activates FAO, while inhibition of the HIF1α-HK2 pathway drives glycolysis inhibition. The modulations of these pathways by AMPK contribute to inhibiting PMT.

Conclusions: Metabolic reprogramming controls the fate of pericyte transdifferentiation and targets the abnormal metabolism of pericytes can effectively prevent AKI to CKD transition.

Comments:

Summary: This study aimed to investigate the role of metabolic reprogramming in the transition of pericytes to myofibroblasts, a process known as pericyte-myofibroblast transition (PMT). The researchers used a mouse model of acute kidney injury (AKI) to chronic kidney disease (CKD) and treated pericyte-like cells with TGF-β to simulate PMT. They examined the levels of fatty acid oxidation (FAO) and glycolysis and studied the signaling pathways involved in PMT under the influence of drugs that regulate metabolic reprogramming.

The results showed that PMT is characterized by a decrease in FAO and an increase in glycolysis. The researchers found that enhancing FAO using the peroxisome proliferator-activated receptor gamma coactivator-1α (PGC1α) activator ZLN-005 or suppressing glycolysis using the hexokinase 2 (HK2) inhibitor 2-DG inhibited PMT and prevented the transition from AKI to CKD. They also identified the involvement of the AMP-activated protein kinase (AMPK) in modulating the metabolic switch from glycolysis to FAO. Specifically, the PGC1α-CPT1A pathway was responsible for activating FAO, while the HIF1α-HK2 pathway drove glycolysis inhibition. AMPK played a role in regulating these pathways and contributed to inhibiting PMT.

Based on these findings, the researchers concluded that metabolic reprogramming plays a crucial role in controlling the fate of pericyte transdifferentiation and that targeting the abnormal metabolism of pericytes could effectively prevent the transition from AKI to CKD. These findings provide insights into the underlying mechanisms of PMT and suggest potential therapeutic strategies for managing AKI and CKD.