Sepsis-associated acute kidney injury (S-AKI) is a frequent, severe complication of sepsis with high morbidity and mortality and limited therapeutic options. This study aimed to define the role of SIRT2 in renal injury and inflammation during S-AKI and to test whether inhibiting SIRT2 could attenuate injury. The investigators focused on post-translational regulation of the sialidase NEU1 and downstream effects on CD44/PI3K/AKT signaling as a potential protective mechanism.
S-AKI was modeled using lipopolysaccharide (LPS) exposure in mice and in cultured renal tubular epithelial cells. The in vivo experiments compared wild-type with SIRT2 whole-body knockout mice. In vitro work used the human proximal tubular cell line HK-2 with SIRT2 knockdown and SIRT2 overexpression to assess cell-autonomous effects.
Outcomes included renal histopathology, biochemical markers of renal injury, levels of pro-inflammatory cytokines, macrophage infiltration, and measures of cell death. Molecular studies evaluated NEU1 acetylation status and sialidase activity, CD44 sialylation and binding to hyaluronic acid (HA), and activation of the downstream PI3K/AKT signaling cascade.
Pharmacological inhibition used the selective SIRT2 inhibitor AGK2. A nanotechnology-based formulation (referred to as Nano-AGK2) was also tested to determine whether enhanced renal delivery altered therapeutic efficacy.
SIRT2 whole-body knockout substantially alleviated renal damage in the LPS-induced S-AKI mouse model. Knockout animals exhibited reduced histological injury and lower levels of pro-inflammatory cytokines compared with wild-type controls in the context of LPS challenge. These findings indicate that loss of SIRT2 activity confers protection against the inflammatory and tissue-damaging consequences of endotoxin-driven S-AKI.
In HK-2 cells, targeted knockdown of SIRT2 attenuated LPS-induced inflammatory responses and reduced cell death, indicating a cell-intrinsic protective effect when SIRT2 is suppressed. Conversely, overexpression of SIRT2 amplified inflammatory signaling and increased cell death after LPS exposure. These complementary in vitro results support the genetic loss-of-function data from mice and suggest SIRT2 activity promotes tubular epithelial inflammation and injury in S-AKI.
Mechanistic studies identified NEU1 as a substrate of SIRT2-mediated deacetylation. Specifically, SIRT2 deacetylates NEU1 at lysine 395. Inhibition or genetic loss of SIRT2 resulted in NEU1 hyperacetylation, which correlated with reduced NEU1 sialidase enzymatic activity.
Reduced NEU1 activity increased the degree of sialylation on CD44, enhancing CD44/HA (hyaluronic acid) binding. This change in CD44 sialylation state and ligand interaction promoted activation of the downstream PI3K/AKT signaling pathway. The authors link this signaling axis — from NEU1 acetylation to CD44 sialylation to PI3K/AKT activation — with the observed protection against renal injury in S-AKI models.
Pharmacological blockade of SIRT2 using the selective inhibitor AGK2 mitigated LPS-induced renal injury and reduced inflammatory markers in the mouse S-AKI model, mirroring the effects seen with genetic deletion. The study also tested a nano-formulation, Nano-AGK2, which demonstrated enhanced renal accumulation relative to free AGK2 and produced greater therapeutic efficacy in this experimental context.
The abstract reports that Nano-AGK2 improved renal delivery and outcome measures compared with free AGK2, supporting formulation-based strategies to increase kidney-targeted exposure for SIRT2 inhibitors. Specific dosing, pharmacokinetic parameters, safety endpoints, and numerical efficacy results were not reported in the abstract.
These results identify SIRT2 as a post-translational regulator of NEU1 and implicate SIRT2 activity in promoting inflammation and renal tubular cell death in LPS-induced S-AKI. Inhibition of SIRT2—genetically or pharmacologically—leads to NEU1 hyperacetylation, attenuated NEU1 sialidase activity, increased CD44 sialylation and CD44/HA binding, and activation of PI3K/AKT signaling associated with renal protection.
The authors propose that SIRT2 inhibition may represent a potential therapeutic strategy for S-AKI and provide preclinical evidence supporting further investigation. The abstract does not include detailed numeric results, dosing information, long-term outcomes, or safety data; these details were not reported in the source abstract and would be needed to inform translational planning.