Targeting HMGB1: A Potential Therapeutic Strategy for Chronic Kidney Disease

Abstract

High-mobility group protein box 1 (HMGB1) is a member of a highly conserved high-mobility group protein present in all cell types. HMGB1 plays multiple roles both inside and outside the cell, depending on its subcellular localization, context, and post-translational modifications. HMGB1 is also associated with the progression of various diseases. Particularly, HMGB1 plays a critical role in CKD progression and prognosis. HMGB1 participates in multiple key events in CKD progression by activating downstream signals, including renal inflammation, the onset of persistent fibrosis, renal aging, AKI-to-CKD transition, and important cardiovascular complications. More importantly, HMGB1 plays a distinct role in the chronic pathophysiology of kidney disease, which differs from that in acute lesions. This review describes the regulatory role of HMGB1 in renal homeostasis and summarizes how HMGB1 affects CKD progression and prognosis. Finally, some promising therapeutic strategies for the targeted inhibition of HMGB1 in improving CKD are summarized. Although the application of HMGB1 as a therapeutic target in CKD faces some challenges, a more in-depth understanding of the intracellular and extracellular regulatory mechanisms of HMGB1 that underly the occurrence and progression of CKD might render HMGB1 an attractive therapeutic target for CKD.

Keywords: AKI-to-CKD transition; CKD; HMGB1; renal homeostasis; therapeutic strategy.

Figure 1

Timeline of landmark achievements of HMGB1 in CKD in the past 50 years.

Figure 2

Structure and redox reaction of HMGB1. (HMGB1 is composed of A-box, B-box, C-terminal acidic tail, and a short but functionally significant N-terminal region, with nuclear localization signals and three redox-sensitive cysteine residues. HMGB1 can be classified into three subtypes: fully reduced HMGB1, disulfide HMGB1, and fully oxidized HMGB1.)

Figure 3

The distribution and function of HMGB1. (HMGB1 can cross organelles from the nucleus at higher concentrations into the cytoplasm in response to stress injury. The function of HMGB1 is related to its subcellular structure. In the nucleus, HMGB1 plays an important role in DNA replication and repair, chromatin remodeling, nucleosome assembly, and telomere maintenance; In the cytoplasm, HMGB1 is primarily involved in regulating autophagy, mitochondrial function, and apoptosis; Extracellular HMGB1 primarily serves as a DAMP and participates in many immune responses, can also promote cell migration and proliferation.)

Figure 4

HMGB1 and renal homeostasis. (HMGB1 is expressed in a variety of kidney cell types, especially in proximal tubule epithelial cell and podocyte. In case of injury, renal tubular epithelial cells and podocytes are the main sources of HMGB1, and mesangial and endothelial cells also express HMGB1. HMGB1 mediates kidney damage and repair through multiple pathways to maintain renal homeostasis.)

Figure 5

Pathogenic roles of HMGB1 in CKD. (HMGB1 plays an important role in kidney disease, especially in CKD, including kidney inflammation, fibrosis, ageing, AKI-to-CKD transition, vascular calcification, and renal replacement therapy. Several HMGB1 inhibitors and hemodialysis have shown potential therapeutic effects in improving CKD.)