Postischemic inactivation of HIF prolyl hydroxylases in endothelium promotes maladaptive kidney repair by inducing glycolysis
Ratnakar Tiwari, … , Navdeep S. Chandel, Pinelopi P. Kapitsinou
Ratnakar Tiwari, … , Navdeep S. Chandel, Pinelopi P. Kapitsinou
Published December 2, 2024
Citation Information: J Clin Invest. 2025;135(3):e176207. https://doi.org/10.1172/JCI176207.
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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 8

Post-IRI treatment with the MCT4 inhibitor syrosingopine restores adaptive kidney repair in PHDTiEC mice.

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Post-IRI treatment with the MCT4 inhibitor syrosingopine restores adapti...
(A) Representative images of immunofluorescence staining for MCT4 (red) and EMCN (green) of contralateral and day 14 postischemic kidneys from PHDTiEC mice. Zoom-in panels show the increased expression of MCT4 in EMCN+ve cells in PHDTiEC postischemic kidney. Images were captured using a Nikon Ti2 Widefield fluorescence microscope. Scale bar: 100 μm. (B) Schematic illustrates the timing of unilateral renal artery clamping, tamoxifen administration, treatment with syrosingopine, and analysis at day 14 after uIRI. (C) Representative images of uninjured kidney compared with day 14 postischemic kidneys treated with vehicle or syrosingopine. All mice are PHDTiEC mutants. (D) Representative images of H&E- and Picrosirius red–stained day 14 postischemic kidneys from vehicle- versus syrosingopine-treated PHDTiEC mutants. Right: tubular injury score and semiquantitative analysis of Picrosirius red+ve area of day 14 postischemic kidneys for the indicated experimental groups. Scale bars: 100 μm (H&E); 200 μm (Picrosirius red). (E) mRNA levels of Loxl2, Tgfb1, and Acta2 in CTL and IR kidneys from vehicle- or syrosyngopine-treated PHDTiEC mice on day 14 after uIRI. Data are represented as mean ± SEM. For D, statistics were determined by unpaired t test with Welch’s correction. For E, statistics were determined using 1-way ANOVA with Šidák’s correction for multiple comparisons. n = 4–6. *P < 0.05; ***P < 0.001. veh, vehicle; Syro, syrosingopine.