Potential Therapeutic Target for Ischemic Acute Kidney Injury Discovered

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Pinelopi Kapitsinou, MD, associate professor of Medicine in the Division of Nephrology and Hypertension, was senior author of the study published in the Journal of Clinical Investigation.

Investigators led by Pinelopi Kapitsinou, MD, associate professor of Medicine in the Division of Nephrology and Hypertension, have discovered that inhibiting the hypoxia-driven MCT4 protein may halt the progression of acute kidney injury to chronic kidney disease, according to a recent study published in the Journal of Clinical Investigation.

Ischemic acute kidney injury, resulting from the reduction of blood flow to the kidneys, commonly affects hospitalized patients, particularly in older individuals with comorbidities such as diabetes. There are currently no approved treatments for acute kidney injury and the kidneys’ failure to recover may progress to chronic kidney disease, highlighting a large unmet need for patients, Kapitsinou said.

“In severe cases of acute kidney injury, dialysis may be required, but it serves only as a bridge until the kidneys recover. The challenge is that we currently lack treatments to accelerate kidney recovery, leaving us to rely on supportive care while waiting for the kidneys to heal on their own, though sometimes they don’t,” Kapitsinou said.

Previous work has suggested that the impaired function of endothelial cells – cells which line blood vessels and serve as a protective barrier – may contribute to the transition of acute kidney injury to chronic kidney disease. However, the precise underlying mechanisms have remained poorly understood.

In the current study, Kapitsinou’s team analyzed kidney endothelial cells from both mouse models of ischemic acute kidney injury and samples from patients with ischemic acute kidney injury.

“We conducted gain-of-function and loss-of-function studies to better understand how the hypoxia machinery in the endothelial cells dictates responses to ischemic acute kidney injury,” Kapitsinou said.

Using functional genomics, the scientists discovered that the endothelial oxygen sensing prolyl hydroxylase domain (PHD) enzymes 1, 2 and 3 play a key role in regulating post-ischemic kidney repair. Post-ischemic inactivation of the PHD1, PHD2, and PHD3 enzymes in endothelial cells induced hypoxia and glycolysis, leading to more fibrosis and inflammation.

Next, using single-cell RNA sequencing, the investigators discovered that PHD1-, PHD2- and PHD3-deficient kidney endothelial cells also showed upregulation of the SLC16A3 gene. This gene encodes the monocarboxylate transporter 4 (MCT4) protein, which helps release lactate from cells, and has also found to be increased in the kidney endothelium of patients with severe acute kidney injury.

“This protein caught our attention because recently it has been implicated as being important to regulate the glycolytic process and studied as a target in cancer biology. Based on this, we hypothesized that inhibiting MCT4 could suppress glycolysis, potentially influencing the responses observed in the post-ischemic kidney,” Kapitsinou said.

To test their hypothesis, the scientists treated the mouse models with the MCT4 inhibitor syrosingopine and discovered that inhibiting MCT4 restored successful kidney repair in the mice and suppressed pro-inflammatory endothelial cell activation.

Their findings suggest that MCT4 may be a promising therapeutic target for inhibiting the transition of acute kidney injury to chronic kidney disease.

Moving forward, Kapitsinou said her team aims to investigate how metabolic reprogramming through MCT4 inhibition is linked to endothelial function.

“Right now, our studies show that MCT4 inhibition probably affects maladaptive inflammatory pathways. However, further investigation is needed to better understand this mechanism and facilitate its effective translation to humans,” Kapitsinou said.

Co-authors of the study include Matthew Schipma, PhD, research assistant professor of Biochemistry and Molecular Genetics; Benjamin Thomson, ‘15 PhD, assistant professor of Ophthalmology; Nicolae Valentin David, PhD, the Frank Krumlovsky, MD, Professor of Medicine; Susan Quaggin, MD, chair and the Irving S. Cutter Professor of Medicine; Edward Benjamin Thorp, PhD, the Frederick Robert Zeit Professor of Pathology; and Navdeep Chandel, PhD, the David W. Cugell, MD, Professor of Medicine in the Division of Pulmonary and Critical Care and of Biochemistry and Molecular Genetics.

This work was supported by National Institutes of Health (NIH) grants R01DK115850 and R01DK132672 and an American Heart Association post-doctoral fellowship 23POST1020467.