Post-ischemic inactivation of HIF prolyl hydroxylases in endothelium promotes maladaptive kidney repair by inducing glycolysis

Tiwari, R.; Sharma, R.; Rajendran, G.; Borkowski, G. S.; An, S. Y.; Schonfeld, M. P.; O'Sullivan, J.; Schipma, M.; Zhou, Y.; Courbon, G.; David, V.; Quaggin, S. E.; Thorp, E. B.; Chandel, N. S.; Kapitsinou, P. P.

doi:10.1101/2023.10.03.560700

bioRxiv · 10.1101/2023.10.03.560700

Post-ischemic inactivation of HIF prolyl hydroxylases in endothelium promotes maladaptive kidney repair by inducing glycolysis

Tiwari, R.·Sharma, R.·Rajendran, G.·Borkowski, G. S.·An, S. Y.·Schonfeld, M. P.·O'Sullivan, J.·Schipma, M.·Zhou, Y.·Courbon, G.·David, V.·Quaggin, S. E.·Thorp, E. B.·Chandel, N. S.·Kapitsinou, P. P.

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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 post-ischemic kidney repair. In renal endothelium, we observed compartment-specific differences in the expression of the three PHD isoforms in both mice and humans. We found that post-ischemic concurrent inactivation of endothelial PHD1, PHD2, and PHD3 but not PHD2 alone promoted maladaptive kidney repair characterized by exacerbated tissue injury, fibrosis, and inflammation. Single-cell RNA-seq analysis of the post-ischemic endothelial PHD1, PHD2 and PHD3 deficient (PHDTiEC) kidney revealed an endothelial glycolytic transcriptional 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 pro-inflammatory EC activation reducing monocyte-endothelial cell interaction. Our findings suggest avenues for halting AKI to CKD transition based on selectively targeting the endothelial hypoxia-driven glycolysis/MCT4 axis.

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Tiwari, R., Sharma, R., Rajendran, G., Borkowski, G. S., An, S. Y., Schonfeld, M. P., O'Sullivan, J., Schipma, M., Zhou, Y., Courbon, G., David, V., Quaggin, S. E., Thorp, E. B., Chandel, N. S., Kapitsinou, P. P.. 2023-10-03. Post-ischemic inactivation of HIF prolyl hydroxylases in endothelium promotes maladaptive kidney repair by inducing glycolysis. https://doi.org/10.1101/2023.10.03.560700

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