# Endothelial oxygen sensing and metabolic reprogramming in AKI to CKD transition > **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2024 · $549,821 ## Abstract PROJECT SUMMARY Ischemic acute kidney injury (AKI) often progresses to chronic kidney disease (CKD) through maladaptive repair. Hypoxia, present in both AKI and CKD, triggers a response mediated by the oxygen sensing prolyl-4-hydroxylase domain-containing proteins (PHD1-3), regulating Hypoxia- Inducible-Factors (HIF). Despite the critical role of endothelial cells in responding to hypoxic injury, the molecular mechanisms by which PHDs in these cells impact post-ischemic kidney repair remain unclear. This knowledge gap is significant, given the pressing need for therapies preventing AKI to CKD transition. Our recent studies on mice and humans revealed compartment- specific differences in PHD isoform expression in the kidney vascular endothelium. Using genetic approaches, we found that concurrent inactivation of endothelial PHD1, PHD2, and PHD3 promotes maladaptive kidney repair, leading to tissue injury, fibrosis, and inflammation. Single- cell RNA-seq analysis showed endothelial hypoxic and glycolytic signatures, which were also observed in severe human 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 and suppressed EC-derived proinflammatory responses. Finally, among the three PHD isoforms, we identified endothelial PHD3 as the critical isoform regulating post-ischemic kidney fibrosis. The goal of this proposal is to build on these exciting discoveries and harness hypoxic signaling-dependent mechanisms regulating endothelial cell glycolysis/MCT4 signaling to inhibit AKI to CKD transition. Our central hypothesis is that endothelial PHD3 activity promotes adaptive kidney repair by inhibiting endothelial pro-inflammatory responses through suppression of HIF-driven glycolysis/MCT4 axis. We propose two Aims: (Aim 1) Inhibition of the endothelial MCT4 axis promotes adaptive kidney repair following ischemic AKI by inducing favorable metabolic reprogramming; (Aim 2) Endothelial PHD3 promotes adaptive kidney repair following ischemic AKI by suppressing endothelial derived pro-inflammatory responses through HIF1. The proposed research is innovative because it is the first to investigate the mechanistic basis and therapeutic potential of endothelial hypoxic dependent glycolysis/MCT4 axis in post-ischemic kidney repair using novel genetic models in conjunction with sophisticated transcriptomic and metabolic approaches. Completion of this project will open new avenues of targeted therapeutic possibilities to prevent AKI to CKD transition. ## Key facts - **NIH application ID:** 10977990 - **Project number:** 2R01DK115850-06A1 - **Recipient organization:** NORTHWESTERN UNIVERSITY - **Principal Investigator:** Pinelopi P. Kapitsinou - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $549,821 - **Award type:** 2 - **Project period:** 2017-12-07 → 2028-05-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10977990 ## Citation > US National Institutes of Health, RePORTER application 10977990, Endothelial oxygen sensing and metabolic reprogramming in AKI to CKD transition (2R01DK115850-06A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10977990. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*