From metabolic regulation to kidney protection: β-arrestin 2 as a dual-function therapeutic target

Abstract

We are deeply interested in the recent findings on β-arrestin 2. Liu et al demonstrated that β-arrestin 2 knockout provides significant protection in diabetic nephropathy, underscoring its potential as a promising therapeutic target for diabetic nephropathy treatment. Furthermore, the role of β-arrestin 2 in metabolic regulation is equally critical, particularly in insulin signaling, hepatic glucose production, and adipose tissue function. Although β-arrestin 2 plays a distinct role in metabolism and kidney protection, its tissue-specific regulation opens up valuable avenues for developing targeted therapeutic strategies centered on β-arrestin 2.

Key Words: Type 2 diabetes; Diabetic nephropathy; β-arrestin 2; β-arrestin 1; Metabolic regulation; Tissue-specific signaling; Therapeutic strategies; Multi-target therapies

Core Tip: This article highlights the dual-function potential of β-arrestin 2 as a therapeutic target for both diabetic nephropathy and metabolic regulation. Recent findings by Liu et al demonstrated that β-arrestin 2 exacerbates kidney damage in diabetic nephropathy by promoting glomerular endothelial cell apoptosis via the endoplasmic reticulum stress pathway. Conversely, β-arrestin 2 plays a significant role in regulating metabolic processes, such as hepatic glucose production, insulin secretion, and adipose tissue function. Its tissue-specific effects make β-arrestin 2 a promising target for therapeutic strategies, with ongoing advancements in biased ligands, small molecule modulators, and RNA aptamers.

TO THE EDITOR

We read with great interest the high-quality paper by Liu et al[1] published in the World Journal of Diabetes. This study focuses on the mechanisms of glomerular endothelial cell (GENC) injury in the early stages of diabetic nephropathy (DN), revealing that β-arrestin 2 expression is upregulated in GENCs. The upregulation of β-arrestin 2 activates the ATF6-mediated endoplasmic reticulum stress pathway, promoting GENC apoptosis and exacerbating kidney injury in DN mice. Conversely, silencing β-arrestin 2 using AAV-shRNA-β-arrestin 2 successfully alleviated kidney injury in DN mice. This study offers a new perspective for the treatment of DN.

CRITICAL ROLES OF β-ARRESTIN 2 AND β-ARRESTIN 1 IN METABOLIC REGULATION

The β-arrestin family consists of two members, β-arrestin-1 and β-arrestin 2, which are widely expressed throughout the body[2]. Studies have shown that β-arrestin 2 can bind to and regulate the activity of hundreds of different G protein-coupled receptors (GPCRs)[3]. Over the past decade, an increasing number of studies have suggested that β-arrestins also possess signaling functions independent of GPCR regulation. As a multifunctional signaling regulator, β-arrestin 2 is involved in various metabolic processes, such as hepatic glucose production (HGP), pancreatic β-cell function, and adipose tissue regulation.

HGP is a key feature of type 2 diabetes. The glucagon receptor in the liver plays an important role, and hepatocyte-specific expression of β-arrestin 2 significantly reduces glucagon receptor signaling, thereby inhibiting HGP[4]. Simultaneously, under a high-fat diet, hepatocyte-specific knockout of β-arrestin 2 exacerbated metabolic disturbances, whereas overexpression of β-arrestin 2 significantly improved blood glucose levels and glucose tolerance[3]. In pancreatic β-cells, knockdown of β-arrestin 2 resulted in impaired glucose-stimulated insulin secretion and difficulties in calcium ion influx, indicating severe metabolic defects[5]. Under ‘glucolipotoxic’ conditions, the level of β-arrestin 2 is significantly decreased in human islets[5]. In animal models, β-arrestin 2-knockout mice fed with a high-fat diet exhibited glucose intolerance. Interestingly, selective depletion of β-arrestin 2 in adipose tissue affected the browning of white adipose tissue by regulating β3-adrenergic receptor signaling, thereby influencing body fat accumulation and energy metabolism[6]. In mice with insulin resistance and impaired glucose tolerance, β-arrestin 2 knockout alleviates metabolic disorders[6]. In addition, the expression levels of β-arrestin 1 and β-arrestin 2 were increased in podocytes under a DN environment, and they were further found to inhibit the autophagy process in podocytes through negative regulation of ATG12-ATG5 binding. It is evident that β-arrestin 2 plays a multifunctional role in metabolic regulation and disease, with its effects spanning multiple organ systems and involving various pathways.

β-arrestin 1 and β-arrestin 2 have distinct metabolic regulatory functions. For instance, under a high-fat diet, β-arrestin 2 knockout in mouse hepatocytes leads to metabolic disturbances, whereas β-arrestin 1 knockout does not exhibit significant metabolic disruption phenotypes[4]. In addition, study by Liu et al[1] demonstrated that in the GENCs of DN mice, β-arrestin 2 expression was significantly upregulated, whereas β-arrestin 1 expression was not significantly altered. However, other studies have found that both β-arrestin 1 and β-arrestin 2 are upregulated in DN, and knockout of either β-arrestin 1 or β-arrestin 2 can alleviate autophagy defects and filtration barrier damage[7].

CHALLENGES AND OPPORTUNITIES OF TISSUE-SPECIFIC REGULATION

Over the past decade, in-depth research on β-arrestin 2 has revealed its contrasting roles in different tissues, which necessitates careful consideration of its unique functions in each tissue when developing targeted therapeutics. The widespread expression of β-arrestin 2 in various tissues poses a challenge in achieving therapeutic specificity. In patients with DN and mouse models, the expression of β-arrestin 2 is typically upregulated, accompanied by varying degrees of renal function impairment. Tissue-specific knockout of β-arrestin 2 in animal models can clarify its functional differences in the liver, pancreas, and kidneys, providing a foundation for the development of precise therapeutic strategies[8]. In addition, the use of multi-omics technologies (transcriptomics, proteomics, and metabolomics) combined with time-series experiments and disease staging models can provide a comprehensive analysis of the signaling regulatory networks of β-arrestin 2 at different disease stages. This approach will help reveal its dynamic roles and guide personalized therapeutic strategies[9].

Currently, significant progress has been made in drug development targeting β-arrestin 2, including biased ligands, small molecule modulators, and RNA aptamers. Biased antagonists function through the allosteric modulation mechanism of GPCRs. Specifically, ligands must bind to different receptor sites, selectively blocking certain signaling pathways while preserving others, thereby reducing adverse side effects[10]. A novel class of biased agonists was developed based on the mu-opioid receptor and angiotensin II type 1 receptor to manage pain and heart failure[11]. Furthermore, small molecules targeting specific β-arrestin subunits may enable the modulation of particular signaling pathways to achieve therapeutic outcomes. Barbadin binds to β2-adaptin, inhibiting the interaction between β-arrestin and the β2 subunit of the clathrin adaptor protein AP2, thereby interfering with the internalization process of GPCRs without affecting β-arrestin recruitment[9]. Successful targeting of β-arrestin 2 through RNA aptamers (a class of oligonucleotide structures that bind to target proteins with high specificity) inhibited β-arrestin 2 activity and blocked several tumor signaling pathway, such as the successful reduction of leukemia cell tumorigenicity through the RNA aptamer system[12]. Finally, developing multi-targeted therapeutic strategies that integrate the regulation of β-arrestin 2 (combining antidiabetic drugs, antioxidants, and anti-inflammatory drugs) will help to address the complex interactions between metabolic disorders and renal pathology, opening innovative avenues for the treatment of complex diseases.

CONCLUSION

In summary, the study by Liu et al[1] on β-arrestin 2 in DN provides a novel perspective, revealing that β-arrestin 2 promotes GENC apoptosis by regulating the endoplasmic reticulum stress pathway. β-arrestin 2 plays a crucial role in metabolic regulation, including involvement in gluconeogenesis, insulin secretion, and adipose tissue energy metabolism. In recent years, drug development targeting β-arrestin 2 has made progress, such as biased agonists, small molecule modulators, and RNA aptamers. Based on existing research findings, it is essential to further investigate whether the loss of β-arrestin 2 induces compensatory effects through enhanced β-arrestin 1 expression or function and to elucidate the mechanisms underlying their cooperation or interplay in the pathogenesis of DN. Moreover, additional studies are required to explore the dual role of β-arrestin 2 in renal pathology and metabolic dysfunction as well as to advance the development of multi-target therapeutic strategies. Clarifying the tissue-specific roles of β-arrestin 2 under various physiological and pathological conditions has the potential to be an effective therapeutic target for complex diseases.

ACKNOWLEDGEMENTS

We thank the reviewers for their comments that helped to improve the manuscript.