Interferon-Stimulated Genes: Novel Targets in Renal Pathogenesis

Abstract

Background: Kidney diseases are a prevalent global health concern, and despite ongoing research, there remains a lack of fully effective clinical treatments to prevent or halt their progression. Consequently, it is encouraged to identify novel biomarkers, establish early diagnostic methods, pinpoint key molecular pathways, and develop innovative therapeutic targets for more effective management of renal disorders.

Summary: Interferons (IFNs), a group of cytokines, play pivotal roles in immune responses, particularly in antiviral and antiproliferative activities. IFNs trigger a cascade of signaling events that lead to the induction of interferon-stimulated genes (ISGs), which are essential for controlling viral infections and regulating immune responses. This review explores the impact of interferon-related genes on renal disorders, focusing on the mechanisms, therapeutic approaches, and consequences of enhanced interferon signaling in the kidney.

Key messages: Most diagnostic and therapeutic strategies targeting ISGs are still far from clinical implementation. The better understanding of ISG-regulated pathophysiology and the progress of new intervention approaches are expected to facilitate the clinical translation of ISGs-based diagnosis and therapy of kidney diseases.

Keywords: Immune regulation; Interferon signaling; Interferon-stimulated genes; Renal pathogenesis; Therapeutic target.

Fig. 1.

Simplified overview of ISGs and their actions in kidney diseases. ISGs play a crucial role in kidney diseases. dsRNA, a common viral signature, triggers the activation of ISGs through pathways such as JAK/STAT and PKR. This activation cascade leads to a series of pathological events in the kidney, including tubular injury, fibrosis, and ER stress. Among the ISGs, ISG15 stands out for its significant contribution to fibrosis promotion and cellular proliferation. Additionally, ISG56 and OAS1 have been implicated in glomerular damage. The intricate interplay between these ISGs and their downstream effects underscores the complex nature of kidney pathology, suggesting that ISGs may serve as novel therapeutic targets in the treatment of kidney injury.

Fig. 2.

Therapeutic agents targeting ISGs. The JAK/STAT signaling pathway, activated by various stimuli, leads to the expression of ISGs such as ISG15, ISG20, and PKR, which have been implicated in various forms of kidney injury. ISG15 is associated with CKD, UUO, and AKI, while ISG20 plays a role specifically in AKI. PKR, which can be inhibited by imoxin, contributes to kidney injury in L-NAME-induced models. Targeting this pathway with JAK inhibitors like ruxolitinib and baricitinib offers promising therapeutic potential by disrupting the cascade that leads to ISG expression and subsequent renal damage. These findings highlight the importance of ISGs as therapeutic targets and underscore the potential of pathway-specific inhibitors in mitigating kidney injury and fibrosis.