Kidney Week

Abstract: FR-PO0346

Role of Endothelial Lactate Monocarboxylate Transporter (MCT1/4) in AKI Repair

Session Information

• AKI: Mechanisms - Metabolism and Repair
  October 23, 2026 | Location: Exhibit Hall A, 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

Rajni Sharma, MS, MSc, PhD

• O'Sullivan, James, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

James O'Sullivan, PhD

• Tiwari, Ratnakar, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Ratnakar Tiwari, PhD

• Zhou, Yalu, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Yalu Zhou, MS, MSc

• Masuyama, Satoshi, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Satoshi Masuyama, MD, PhD

• Kapitsinou, Pinelopi P., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Pinelopi P. Kapitsinou, MD

Background

Metabolic reprogramming drives maladaptive repair during the AKI-CKD transition, yet endothelial metabolic changes remain poorly defined. We previously identified MCT4 as a regulator of hypoxia-induced endothelial glycolysis. Here we demonstrate that endothelial MCT4 is a critical mediator of maladaptive repair after ischemic AKI.

Methods

WT C57BL/6J male mice underwent unilateral ischemia-reperfusion injury (uIRI) and received the MCT4 inhibitor syrosingopine (syro, 7.5 mg/kg) or vehicle. scRNAseq was performed on days 7 and 14 post-uIRI. For endothelial-specific MCT4 deletion, Cdh5(PAC)-CreER;MCT4^flox/flox mice (MCT4iEC) were subjected to uIRI with histological and molecular analyses on day 14. Human PPAECs subjected to hypoxia-reoxygenation plus IL1β stimulation underwent metabolomic analysis after 24-hour of syro treatment. snRNAseq from patients with AKI was analyzed for MCT4 expression.

Results

In wild-type mice subjected to unilateral IRI, Slc16a3 mRNA (encoding MCT4) was 4-fold upregulated in whole kidney lysates at Day 7 post-IRI (P<0.001). Immunohistochemistry confirmed induction of MCT4 in kidney endothelial cells. Pharmacologic inhibition of MCT4 with syro reduced renal fibrosis and inflammation post uIRI. scRNAseq at day 14 showed that syro reduced pro-inflammatory macrophage clusters, while endothelial clusters showed suppression of IFNα/IFNγ pathways along with enrichment of pyruvate metabolism and TCA cycle pathways. Endothelial-specific MCT4 deletion recapitulated this protection: MCT4iEC mice showed reduced fibrotic area (30%, P<0.001), lower injury scores (3.6 vs. 2.8, P<0.05), and decreased Loxl2 (1.3-fold) and Tgfb1 (1.6-fold) expression versus controls (n=6–8, P<0.05). In vitro metabolomics of syro treated endothelial cells showed enrichment of purine/pyrimidine metabolism as well as pyruvate and TCA cycle pathways. Finally, snRNAseq from AKI patients demonstrated increased MCT4 expression in kidney endothelial cells supporting the clinical relevance of our findings.

Conclusion

Endothelial MCT4 drives post-ischemic metabolic maladaptation. Its genetic deletion or pharmacologic inhibition reprograms endothelial metabolism from glycolytic, pro-inflammatory states toward oxidative pathways, reducing fibrosis and promoting renal recovery. These findings establish endothelial MCT4 as a therapeutic target for preventing AKI-to-CKD progression.

Funding

• NIDDK Support