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Thymosin β4 alleviates sepsis-associated acute kidney injury by suppressing MAPK signaling pathway

ABSTRACT: Sepsis-associated acute kidney injury (SA-AKI) is a common complication in septic patients and is associated with high mortality and progression to chronic kidney disease (CKD). Previous studies have demonstrated that thymosin β4 (Tβ4) attenuates lipopolysaccharide (LPS)-induced liver injury and ischemic AKI via inhibiting inflammatory response. Here, we aimed to investigate the effects of Tβ4 on SA-AKI and elucidate its underlying mechanisms. In vivo and in vitro models of SA-AKI were established using LPS. Tβ4 was administered 30 min after LPS exposure. Transcriptome sequencing was performed to explore the underlying molecular mechanisms, which were further validated by western blotting in vitro. In SA-AKI mice, serum Tβ4 levels were markedly decreased. Administering Tβ4 significantly ameliorated the renal dysfunction and morphological injury in LPS-treated mice. Consistently, Tβ4 reduced renal inflammation and apoptosis in SA-AKI mice. Transcriptome-sequencing analysis indicated that MAPK signaling pathway was involved in both SA-AKI pathogenesis and the protective effect of Tβ4. Western blotting of the renal tissues confirmed that LPS markedly increased the phosphorylation of JNK1/2, p38 MAPK and ERK1/2, whereas Tβ4 significantly suppressed their activation. Furthermore, pharmacological activation of MAPK pathway with anisomycin abrogated the inhibitory effects of Tβ4 on MAPK signaling in in vitro SA-AKI models. In conclusion, Tβ4 alleviates renal inflammation and apoptosis in SA-AKI by suppressing MAPK signaling pathway. Tβ4 may represent a potential therapeutic strategy for early intervention in SA-AKI.

ORGANISM(S): Mus musculus

PROVIDER: GSE328666 | GEO | 2026/07/16

REPOSITORIES: GEO

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Project description:Sepsis is a severe and dysregulated inflammatory disease that often precedes the development of acute kidney injury (AKI) with consequent worsening outcome. The main characteristics of sepsis-induced AKI include endothelial cell (EC) dysfunction, infiltration of inflammatory cells, glomerular thrombosis, and renal tubular epithelial cells (RTEC) injury. Numerous studies have demonstrated that mammalian target of rapamycin (mTOR) activation has been implicated in the initiation and progression of renal injury in course of sepsis. However, little is known, about the molecular basis of mTOR role in EC and RTEC dysfunction. Here, we evaluate whether mTOR inhibition by Rapamycin (Rp) as potential strategy to ameliorate renal function and dissected the molecular mechanisms involved. In a mouse model of lipopolysaccharide (LPS)-induced AKI , LPS injection led to a time-dependent increase of serum creatinine and significant morphological changes in renal parenchyma associated with increased collagen deposits and endothelial dysfunction. Interestingly, Rp treatment significantly decreased creatine levels and preserved renal parenchyma, counteracting Endothelial-to mesenchymal transition (EndMT) process and early fibrosis through the inhibition of ERK pathway. Next, we examined the effects of LPS-TLR4 interaction in RTECs. Through a whole-genome DNA methylation analysis in cultured RTEC, we found that LPS induced aberrant methylation, particularly in regions involved in premature aging. The most represented genes were CD39 and WFS1. LPS stimulation of RTEC led to up-regulation of SA-β Gal and cell cycle arrest markers such as p21. In accordance, in endotoxemic mice, we found a decreased expression of CD39 concurrent with Klotho down-regulation. Administration of Rp exerted anti-aging effects in endotoxemic mice, preserving CD39 and Klotho expression. In conclusion, we demonstrated that mTOR inhibition could offer novel strategies to protect endothelial and tubular compartment from accelerated aging and fibrosis thus counteracting the progression to chronic kidney disease.

Project description:Sepsis-associated acute kidney injury (SA-AKI) is a critical condition characterized by high morbidity and mortality rates, particularly in intensive care settings. This study focuses on RP105, a pattern recognition receptor, exploring its role in moderating the mechanisms of oxidative stress and ferroptosis during SA-AKI, offering insights into its potential as a therapeutic target. SA-AKI model was established using RP105 knockout (KO) and wild-type (WT) mice through cecal ligation and puncture (CLP). Comprehensive evaluations included the assessment of ferroptosis markers and the expression levels of pro-inflammatory cytokines. RP105 expression was markedly reduced in the kidneys following CLP induction, correlating with worsened renal outcomes. Compared to the Sham group, RP105-/- mice displayed heightened renal damage, increased levels of oxidative stress markers, and enhanced lipid peroxidation. Notably, the deficiency of RP105 led to increased macrophage infiltration and a shift towards pro-inflammatory phenotypes, which further potentiated ferroptosis and exacerbated renal tissue damage. By influencing macrophage behavior and mitigating inflammatory responses. RP105 deficiency exacerbates macrophage-induced inflammation, oxidative stress, and ferroptosis, forming a vicious cycle that leads to more severe renal injury. These findings underscore the pivotal role of RP105 in mitigating oxidative stress and suppressing ferroptosis in the context of SA-AKI through regulation of the HO-1/SLC7A11/GPX4 axis. By preventing macrophage polarization toward a pro-inflammatory phenotype, RP105 alleviates inflammatory responses and tissue damage, highlighting its potential as a therapeutic target. In contrast, RP105 deficiency exacerbates macrophage-driven inflammation, oxidative stress, and ferroptosis, creating a vicious cycle that worsens kidney injury. Thus, RP105 emerges as a promising therapeutic candidate for mitigating sepsis-induced renal damage.

Project description:Background: Pyroptosis plays a critical role in eliminating pathogens and facilitating tissue repair; however, sustained pyroptosis-driven inflammation accelerates kidney injury and disease progression. Thus, elucidating the mechanisms governing pyroptosis is essential for developing effective therapies for inflammatory kidney diseases such as acute kidney injury (AKI), which currently lacks specific treatment options. Methods: Changes in tubular epithelial cells following drug-induced AKI were assessed using single-cell RNA sequencing, immunohistochemistry, and immunofluorescence. Mechanistic insights were obtained through RNA sequencing, genomic manipulation, transcriptomic profiling, luciferase reporter assays, co-immunoprecipitation, and Western blotting. Tubular epithelial cell fate was further evaluated using transgenic mouse models and pharmacological interventions. Results: We identified activating transcription factor 4 (ATF4) as a key regulator of inflammation in drug-induced AKI. As the master regulator of the integrated stress response, ATF4 was markedly upregulated in renal tubules and positively correlated with kidney dysfunction in both human and murine AKI models. The specific deletion of ATF4 in tubular epithelial cells significantly ameliorated kidney dysfunction, inflammation, and mitochondrial apoptosis, whereas ATF4 activation exacerbated these pathological features. Mechanistically, ATF4 suppression inhibited STAT1 phosphorylation and disrupted its interaction with GBP2, thereby attenuating NLRP3 inflammasome activation, preventing tubular epithelial cells' pyroptosis, and improving kidney function. Notably, inhibition of ATF4—either pharmacologically using our prioritized integrated stress response antagonist ERMT1 or through engineered nanobiologics-mediated silencing of tubular epithelial cells—significantly reduced renal inflammation and injury. Conclusions: ATF4 promoted pyroptosis in drug-induced AKI through STAT1–GBP2 signaling.

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Thymosin β4 alleviates sepsis-associated acute kidney injury by suppressing MAPK signaling pathway

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