Abstract: SA-PO0136
Lactate Monocarboxylate Transporter (MCT1/4) Inhibitor Syrosingopine Restores Adaptive Repair in Kidney Injury
Session Information
- AKI: Mechanisms - 3
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Sharma, Rajni, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
- Tiwari, Ratnakar, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
- O'Sullivan, James, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
- Kapitsinou, Pinelopi P., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
Background
Aberrant glycolysis is implicated in maladaptive repair after acute kidney injury (AKI), but therapeutic strategies remain limited. We previously identified MCT4 as a key effector of endothelial hypoxia-induced glycolysis, where its inhibition restored adaptive repair in mice lacking endothelial Prolyl Hydroxylase Domain proteins. Here, we examined whether pharmacologic MCT1/4 inhibition could promote repair in a physiologic context—wild-type mice with intact oxygen sensing subjected to ischemic or obstructive AKI.
Methods
Male C57BL/6J wildtype mice underwent renal unilateral ischemia-reperfusion injury (uIRI) or unilateral ureteral obstruction (UUO). Starting at day 2 post-IRI, mice were injected with the MCT1/4 inhibitor syrosingopine (SYR) 7.5 mg/kg or vehicle every other day. Histological, molecular, bulk/sc-RNAseq and metabolomic analyses were performed 7 and 14 days after uIRI. UUO-kidneys were analyzed on day 8 post surgery.
Results
Syrosingopine restored kidney damage in IR kidneys as shown by downregulation of mRNAs of profibrotic genes Loxl2, Tgfb1 and proinflammatory Vcam1, Icam1 and reduced collagen deposition relative to vehicle (n=5, P<0.05). Flow cytometry analysis of SYR-treated post-IR kidneys also showed significant reduction in monocyte & macrophage infiltration (n=3-4, P<0.01). Similarly, reduced kidney fibrosis was observed in SYR-treated UUO kidneys relative to vehicle controls (n=6, P<0.05, P<0.01). Bulk RNA seq analysis of SYR-treated day 7 and 14 post-IRI kidneys showed significant downregulation of Interferon gamma response and inflammatory pathways (n=4). Hallmark (GSEA) analysis showed restoration of metabolic health, with upregulation of oxidative phosphorylation and fatty acid metabolism pathways in SYR-treated day 14 IR kidneys relative to vehicle. Metabolomic profiling showed enrichment of TCA, pyruvate and fatty acid metabolic pathways in SYR-treated day 7 post-IR kidneys. Sc-RNA seq analysis showed profound cell-specific metabolic changes in SYR-treated kidneys compared to controls, coupled with significant suppression of macrophage clusters.
Conclusion
The MCT1/4 inhibitor syrosingopine reduces AKI to CKD transition by ameliorating fibrosis, inflammation and metabolic dysregulation—highlighting its potential as a novel therapeutic strategy against AKI.
Funding
- NIDDK Support