Hyaluronidase inhibitor sHA2.75 alleviates ischemia-reperfusion-induced acute kidney injury

ABSTRACT

Hyaluronidases (HAases) are enzymes that degrade hyaluronic acid (HA) in the animal kingdom. The HAases-HA system is crucial for HA homeostasis and plays a significant role in biological processes and extracellular matrix (ECM)-related pathophysiological conditions. This study aims to explore the role of inhibiting the HAases-HA system in acute kidney injury (AKI). We selected the potent inhibitor “sHA2.75” to inhibit HAase activity through mixed inhibitory mechanisms. The ischemia-reperfusion mouse model was established using male BALB/c mice (7–9 weeks old), and animals were subjected to subcapsular injection with 50 mg/kg sHA2.75 twice a week to evaluate the effects of sHA2.75 on AKI on day 1, 5 and 14 after ischemia-reperfusion or sham procedure. Blood and tissue samples were collected for immunohistochemistry, biochemical, and quantitative analyses. sHA2.75 significantly reduced blood urea nitrogen (BUN) and serum creatinine levels in AKI mouse models. Expression of kidney injury-related genes such as Kidney injury molecule-1 (KIM-1), Neutrophil Gelatinase-Associated Lipocalin (NGAL), endothelial nitric oxide synthase (eNOS), type I collagen (Col1), type III collagen (Col3), alpha-smooth muscle actin (α-SMA) showed significant downregulation in mouse kidney tissues after sHA2.75 treatment. Moreover, sHA2.75 treatment led to decreased plasma levels of Interleukin-6 (IL-6) proteins and reduced mRNA levels in renal tissues of AKI mice. Inhibitor sHA2.75 administration in the AKI mouse model downregulated kidney injury-related biomarkers and immune-specific genes, thereby alleviating AKI in vivo. These findings suggest the potential use of HAase inhibitors for treating ischemic reperfusion-induced kidney injury.

KEYWORDS:

• Acute kidney injury (AKI)
• hyaluronidase inhibitor
• ischemic reperfusion injury (IRI) model

Disclosure statement

No potential conflict of interest was reported by the author(s)

Authors contribution

YZ and HZ planned and executed experiments and performed statistical analysis. JZ designed the study idea and proposed the experimental plans.

Ethics approval

All patients provided informed consent and the study was approved by the ethics committee of the First Affiliated Hospital of Kunming Medical University with the ethical approval number (2016) NO. 48 and adhered to the World Medical Association Declaration of Helsinki.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/15384101.2024.2309019.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.