Kidney Week 2025 Annual Meeting-Unraveling the Mysteries of AKI: Therapeutic Strategies on the Horizon

Video Transcription

Video Summary

This recorded symposium session on acute kidney injury (AKI) highlighted emerging therapeutic strategies by targeting endothelial metabolism, fibroblast–matrix signaling, mitochondrial pathways, and even spaceflight-related kidney stress.<br /><br />Dr. Penelope Kapitsinou (Northwestern) presented work showing that endothelial oxygen-sensing pathways (PHD–HIF) strongly shape AKI repair outcomes. Endothelial deletion/inhibition of prolyl hydroxylases after ischemia–reperfusion injury increased hypoxia signaling, drove excessive glycolysis, promoted inflammatory adhesion programs, and worsened fibrosis and capillary rarefaction. Human AKI single-cell datasets similarly showed endothelial upregulation of glycolytic genes. Mechanistically, the lactate transporter MCT4 was induced; pharmacologic inhibition with syrosingopine (MCT1/4 inhibitor, more potent for MCT4) improved repair, reduced fibrosis/inflammation, and reprogrammed endothelial metabolism toward oxidative phosphorylation. Endothelial-specific MCT4 knockout was sufficient for benefit. She also identified endothelial PHD3 as an AKI-upregulated isoform that amplifies interferon-γ signaling via HIF-dependent mechanisms.<br /><br />Dr. Dong Zhao (UConn) focused on resident fibroblasts and early extracellular matrix (ECM) remodeling after AKI. Proteomics of decellularized kidney scaffolds identified MFAP2 as an early induced fibroblast-derived ECM protein. Global MFAP2 knockout worsened AKI across models, increasing tubular injury, inflammation, and apoptosis. Mechanistically, MFAP2 loss disrupted mechanosensitive signaling (MAPK/Hippo/LATS1), reduced ESR2 signaling, suppressed the ketogenesis enzyme HMGCS2, lowered ketone production and ATP, and impaired tubular resilience. An ESR2 agonist rescued injury in MFAP2-deficient mice.<br /><br />Dr. Rick Schnellmann described a drug discovery program identifying the serotonin receptor 5-HT2B as a target to induce mitochondrial biogenesis. The selective 5-HT2B antagonist “M1” increased PGC-1α signaling, mitochondrial content, ATP, fatty-acid oxidation proteins, reduced vascular leak, and lessened long-term fibrosis after AKI, with post-injury dosing and efficacy in aging models.<br /><br />Finally, Dr. Keith Hsu reviewed “cosmic kidney injury” risks in space travel. Data from astronauts and “mousetronauts” suggest microgravity and radiation may drive tubular transporter dephosphorylation, distal nephron remodeling, and potentially thrombotic microangiopathy, contributing to markedly elevated kidney stone risk and long-term kidney disease—offering insights relevant to terrestrial stone disease and AKI/CKD mechanisms.

Asset Subtitle

Moderator(s): Lisa Curtis, Karl Nath

Presentation(s):

Targeting Endothelial Metabolism to Enhance Kidney Repair - Pinelopi Kapitsinou
Tubular Cell-Matrix Interactions in AKI: Role of the Fibroblast - Dong Zhou
New Serotonin Targets and Drugs for AKI - Rick Schnellmann
Space Travel and Cosmic Kidney Injury and Disease - Keith Siew

Meta Tag

Date 11/7/2025

Pathway 1 AKI and Critical Care

Pathway 2 Kidney Biology and Physiology

Session ID 507263

Keywords

acute kidney injury

endothelial metabolism

PHD-HIF oxygen sensing

ischemia-reperfusion injury

glycolysis upregulation

MCT4 lactate transporter

syrosingopine

capillary rarefaction

kidney fibrosis

interferon-gamma signaling

MFAP2 extracellular matrix

fibroblast-matrix signaling

ESR2 estrogen receptor beta

5-HT2B antagonist M1

spaceflight cosmic kidney injury