Augmenting the Endogenous RBM3 Response Protects Against Burn-Induced Acute Kidney Injury by Enhancing...

Area of Science:

• Renal physiology and immunology
• Cellular and molecular mechanisms of injury and repair
• Macrophage biology in disease

Background:

• Acute kidney injury (AKI) pathogenesis involves complex macrophage polarization and efferocytosis.
• Regulatory pathways governing M1/M2 macrophage balance in AKI are not fully understood.
• The role of RNA-binding protein 3 (RBM3) in modulating macrophage function during AKI requires investigation.

Purpose of the Study:

• To elucidate the mechanism by which RBM3 influences macrophage polarization and efferocytosis in burn-induced AKI.
• To determine if RBM3 can be therapeutically targeted to mitigate AKI severity.
• To identify downstream targets of RBM3 involved in macrophage reprogramming.

Main Methods:

• Establishment of a standardized scald burn rat model for AKI.
• Assessment of renal function, histopathology, and RBM3 expression via biochemical assays, histology, qRT-PCR, Western blot, and flow cytometry.
• Intervention with adenoviral RBM3, single-cell RNA sequencing, in vitro knockdown, and dual interference experiments to analyze macrophage polarization, efferocytosis, and gene expression (Slfn4).

Main Results:

• Burn injury induced AKI, with peak severity at 48 hours post-injury, correlating with dynamic RBM3 expression.
• RBM3 overexpression significantly improved renal function, reduced tissue damage and inflammation (decreased IL-6, IL-1β, TNF-α), promoted M2 polarization (increased Arg1, decreased CD86/iNOS), and enhanced efferocytosis.
• RBM3 ameliorates AKI by downregulating Slfn4, thereby driving a pro-resolving macrophage phenotype; Slfn4 knockdown mimicked RBM3's protective effects.

Conclusions:

• RBM3 plays a protective role in burn-induced AKI by modulating macrophage polarization and efferocytosis.
• The RBM3-Slfn4 axis is a key mechanism through which RBM3 exerts its renoprotective effects.
• Targeting the RBM3-Slfn4 pathway offers a potential therapeutic strategy for managing AKI.