Postischemic inactivation of HIF prolyl hydroxylases in endothelium promotes maladaptive kidney repair by inducing glycolysis
Ratnakar Tiwari, Rajni Sharma, Ganeshkumar Rajendran, Gabriella S. Borkowski, Si Young An, Michael Schonfeld, James O’Sullivan, Matthew J. Schipma, Yalu Zhou, Guillaume Courbon, Benjamin R. Thomson, Valentin David, Susan E. Quaggin, Edward B. Thorp, Navdeep S. Chandel, Pinelopi P. Kapitsinou
Ratnakar Tiwari, Rajni Sharma, Ganeshkumar Rajendran, Gabriella S. Borkowski, Si Young An, Michael Schonfeld, James O’Sullivan, Matthew J. Schipma, Yalu Zhou, Guillaume Courbon, Benjamin R. Thomson, Valentin David, Susan E. Quaggin, Edward B. Thorp, Navdeep S. Chandel, Pinelopi P. Kapitsinou
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Research Article Metabolism Nephrology

Postischemic inactivation of HIF prolyl hydroxylases in endothelium promotes maladaptive kidney repair by inducing glycolysis

Abstract

Ischemic acute kidney injury (AKI) is common in hospitalized patients and increases the risk for chronic kidney disease (CKD). Impaired endothelial cell (EC) functions are thought to contribute in AKI to CKD transition, but the underlying mechanisms remain unclear. Here, we identify a critical role for endothelial oxygen sensing prolyl hydroxylase domain (PHD) enzymes 1–3 in regulating postischemic kidney repair. In renal endothelium, we observed compartment-specific differences in the expression of the 3 PHD isoforms in both mice and humans. Postischemic concurrent inactivation of endothelial PHD1, PHD2, and PHD3 but not PHD2 alone promoted maladaptive kidney repair characterized by exacerbated tissue injury, fibrosis, and inflammation. scRNA-Seq analysis of the postischemic endothelial PHD1, PHD2, and PHD3-deficient (PHDTiEC) kidney revealed an endothelial hypoxia and glycolysis-related gene signature, also observed in human kidneys with severe AKI. This metabolic program was coupled to upregulation of the SLC16A3 gene encoding the lactate exporter monocarboxylate transporter 4 (MCT4). Strikingly, treatment with the MCT4 inhibitor syrosingopine restored adaptive kidney repair in PHDTiEC mice. Mechanistically, MCT4 inhibition suppressed proinflammatory EC activation, reducing monocyte-EC interaction. Our findings suggest avenues for halting AKI to CKD transition based on selectively targeting the endothelial hypoxia-driven glycolysis/MCT4 axis.

Authors

Ratnakar Tiwari, Rajni Sharma, Ganeshkumar Rajendran, Gabriella S. Borkowski, Si Young An, Michael Schonfeld, James O’Sullivan, Matthew J. Schipma, Yalu Zhou, Guillaume Courbon, Benjamin R. Thomson, Valentin David, Susan E. Quaggin, Edward B. Thorp, Navdeep S. Chandel, Pinelopi P. Kapitsinou

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Figure 5

Postischemic endothelial PHD inactivation induces a hypoxia and glycolysis gene signature in mRECs.

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Postischemic endothelial PHD inactivation induces a hypoxia and glycolys...
(A) Dot plot visualization shows the expression of marker genes used to identify cRECs, mRECs, and EndMT-RECs clusters. (B) GSEA in mRECs of PHDTiEC kidney compared with control. Among the most highly enriched Hallmark pathways were hypoxia and glycolysis. (C) Violin plots show significantly upregulated glycolytic genes in mRECs of PHDTiEC compared with control. Pathway diagram summarizes the functions of upregulated genes (marked by teal boxes) in glycolysis. (D and E) snRNA-Seq analysis of human kidney tissue from patients with severe AKI and controls (n = 6–8). Analysis was performed on publicly available snRNA-Seq data from Christian Hinze et al. (34). (D) Bubble chart for top 10 enriched Hallmark pathways of upregulated DEGs in kidney ECs from patients with severe AKI compared with controls. (E) Box plots show the expression of glycolytic genes in kidney ECs in controls versus AKI patients. The expression levels of glycolytic genes were extracted from the online interface provided by Christian Hinze et al. (https://shiny.mdc-berlin.de/humAKI). CPM, normalized counts per million.