Glycolysis in Peritubular Endothelial Cells and Microvascular Rarefaction in CKD.

KEY POINTS: Peritubular endothelial cells have a hypoglycolytic metabolism in CKD. Restoration of glycolysis in CKD peritubular endothelial cells by overexpressing 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase attenuates microvascular rarefaction and kidney fibrosis. Strategies targeting the metabolic defect in glycolysis in peritubular endothelial cells may be effective in the treatment of CKD. BACKGROUND: Peritubular endothelial cell dropout leading to microvascular rarefaction is a common manifestation of CKD. The role of metabolism reprogramming in peritubular endothelial cell loss in CKD is undetermined. METHODS: Single-cell sequencing and metabolic analysis were used to characterize the metabolic profile of peritubular endothelial cells from patients with CKD and from CKD mouse models. In vivo and in vitro models demonstrated metabolic reprogramming in peritubular endothelial cells in conditions of CKD and its contribution to microvascular rarefaction. RESULTS: In this study, we identified glycolysis as a top dysregulated metabolic pathway in peritubular endothelial cells from patients with CKD. Specifically, CKD peritubular endothelial cells were hypoglycolytic while displaying an antiangiogenic response with decreased proliferation and increased apoptosis. The hypoglycolytic phenotype of peritubular endothelial cells was recapitulated in CKD mouse models and in peritubular endothelial cells stimulated by hydrogen peroxide. Mechanically, oxidative stress, through activating a redox sensor kruppel-like transcription factor 9, downregulated the glycolytic activator 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase expression, thereby reprogramming peritubular endothelial cells toward a hypoglycolytic phenotype. 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase overexpression in peritubular endothelial cells restored hydrogen peroxide–induced reduction in glycolysis and cellular ATP levels and enhanced the G1/S cell cycle transition, enabling peritubular endothelial cells to improve proliferation and reduce apoptosis. Consistently, restoration of peritubular endothelial cell glycolysis in CKD mice, by overexpressing endothelial Pfkfb3, reversed the antiangiogenic response in peritubular endothelial cells and protected the kidney from microvascular rarefaction and fibrosis. By contrast, suppression of glycolysis by endothelial Pfkfb3 deletion exacerbated microvascular rarefaction and fibrosis in CKD mice. CONCLUSIONS: Our study revealed a disrupted regulation of glycolysis in peritubular endothelial cells as an initiator of microvascular rarefaction in CKD. Restoration of peritubular endothelial cell glycolysis in CKD kidney improved microvascular rarefaction and ameliorated fibrotic lesions.