Pyruvate kinase M2 regulates kidney fibrosis through pericyte glycolysis during the progression from acute kidney injury to chronic kidney disease

Abstract

We aimed to investigate the role of renal pericyte pyruvate kinase M2 (PKM2) in the progression of acute kidney injury (AKI) to chronic kidney disease (CKD). The role of PKM2 in renal pericyte‐myofibroblast transdifferentiation was investigated in an AKI‐CKD mouse model. Platelet growth factor receptor beta (PDGFRβ)‐iCreERT2; tdTomato mice were used for renal pericyte tracing. Western blotting and immunofluorescence staining were used to examine protein expression. An 5‐ethynyl‐2′‐deoxyuridine assay was used to measure renal pericyte proliferation. A scratch cell migration assay was used to analyse cell migration. Seahorse experiments were used to examine glycolytic rates. Enzyme‐linked immunoassay was used to measure pyruvate kinase enzymatic activity and lactate concentrations. The PKM2 nuclear translocation inhibitors Shikonin and TEPP‐46 were used to alter pericyte transdifferentiation. In AKI‐CKD, renal pericytes proliferated and transdifferentiated into myofibroblasts and PKM2 is highly expressed in renal pericytes. Shikonin and TEPP‐46 inhibited pericyte proliferation, migration, and pericyte‐myofibroblast transdifferentiation by reducing nuclear PKM2 entry. In the nucleus, PKM2 promoted downstream lactate dehydrogenase A (LDHA) and glucose transporter 1 (GLUT1) transcription, which are critical for glycolysis. Therefore, PKM2 regulates pericyte glycolytic and lactate production, which regulates renal pericyte‐myofibroblast transdifferentiation. PKM2‐regulated renal pericyte‐myofibroblast transdifferentiation by regulating downstream LDHA and GLUT1 transcription and lactate production. Reducing nuclear PKM2 import can reduce renal pericytes‐myofibroblasts transdifferentiation, providing new ideas for AKI‐CKD treatment.

Targeting pyruvate kinase M2 for the treatment of kidney disease

“…PKM1 are predominantly expressed in muscle, mature spermatozoa and central nervous system, while PKM2 is expressed in brain, kidney, lung and spleen ( Alquraishi et al, 2019 ; Puckett et al, 2021 ). PKM2 is the dominant form of PK in kidney tissue ( Alquraishi et al, 2019 ), and a lot of researches have revealed that regulating PKM2 affects kidney disease progression and treatment ( Li et al, 2020a ; Chen et al, 2023 ; Xie et al, 2023 ), highlighting the important role of PKM2 in kidney disease.…”