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 Robert Thomson; Nicolae Valentin David; Susan E. Quaggin; Edward B. Thorp; Navdeep S. Chandel; Pinelopi P. Kapitsinou

doi:10.1172/JCI176207

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 Robert Thomson, Nicolae Valentin David, Susan E. Quaggin, Edward B. Thorp, Navdeep S. Chandel, Pinelopi P. Kapitsinou^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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 (PHD^TiEC) 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.

Original language	English (US)
Article number	e176207
Journal	Journal of Clinical Investigation
Volume	135
Issue number	3
DOIs	https://doi.org/10.1172/JCI176207
State	Published - Feb 3 2025

Funding

This work was supported by National Institutes of Health (NIH) grants R01DK115850 and R01DK132672 (to PPK), and an American Heart Association (AHA) post-doctoral fellowship 23POST1020467 (to RT). We acknowledge the Northwestern University George M. O\u2019Brien Kidney Research Core Center (NU GoKidney), an NIH/NIDDK funded program (P30 DK114857) for their core services and support. Imaging work was performed at the Northwestern University Center for Advanced Microscopy, generously supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. sc-RNA-Seq was conducted at Northwestern University NUSeq Core Facility. Histology services were provided by the Northwestern University Research Histology and Phenotyping Laboratory, which is supported by NCI P30-CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. The funders had no role in study design, data collection, and interpretation, or the decision to submit the work for publication. Graphical abstract was created with BioRender.com.

ASJC Scopus subject areas

General Medicine

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10.1172/JCI176207

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Tiwari, R., Sharma, R., Rajendran, G., Borkowski, G. S., An, S. Y., Schonfeld, M., O’Sullivan, J., Schipma, M. J., Zhou, Y., Courbon, G., Thomson, B. R., David, N. V., Quaggin, S. E., Thorp, E. B., Chandel, N. S., & Kapitsinou, P. P. (2025). Postischemic inactivation of HIF prolyl hydroxylases in endothelium promotes maladaptive kidney repair by inducing glycolysis. Journal of Clinical Investigation, 135(3), Article e176207. https://doi.org/10.1172/JCI176207

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title = "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.",

author = "Ratnakar Tiwari and Rajni Sharma and Ganeshkumar Rajendran and Borkowski, {Gabriella S.} and An, {Si Young} and Michael Schonfeld and James O{\textquoteright}Sullivan and Schipma, {Matthew J.} and Yalu Zhou and Guillaume Courbon and Thomson, {Benjamin Robert} and David, {Nicolae Valentin} and Quaggin, {Susan E.} and Thorp, {Edward B.} and Chandel, {Navdeep S.} and Kapitsinou, {Pinelopi P.}",

note = "Publisher Copyright: {\textcopyright} 2024, Tiwari et al.",

year = "2025",

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doi = "10.1172/JCI176207",

language = "English (US)",

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Tiwari, R, Sharma, R, Rajendran, G, Borkowski, GS, An, SY, Schonfeld, M, O’Sullivan, J, Schipma, MJ, Zhou, Y, Courbon, G, Thomson, BR , David, NV , Quaggin, SE , Thorp, EB , Chandel, NS & Kapitsinou, PP 2025, 'Postischemic inactivation of HIF prolyl hydroxylases in endothelium promotes maladaptive kidney repair by inducing glycolysis', Journal of Clinical Investigation, vol. 135, no. 3, e176207. https://doi.org/10.1172/JCI176207

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T1 - Postischemic inactivation of HIF prolyl hydroxylases in endothelium promotes maladaptive kidney repair by inducing glycolysis

AU - Tiwari, Ratnakar

AU - Sharma, Rajni

AU - Rajendran, Ganeshkumar

AU - Borkowski, Gabriella S.

AU - An, Si Young

AU - Schonfeld, Michael

AU - O’Sullivan, James

AU - Schipma, Matthew J.

AU - Zhou, Yalu

AU - Courbon, Guillaume

AU - Thomson, Benjamin Robert

AU - David, Nicolae Valentin

AU - Quaggin, Susan E.

AU - Thorp, Edward B.

AU - Chandel, Navdeep S.

AU - Kapitsinou, Pinelopi P.

PY - 2025/2/3

Y1 - 2025/2/3

N2 - 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.

AB - 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.

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ER -

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

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