Coxsackievirus A6 infection exacerbates kidney injury in mice through the p38-MAPK pathway

Q: What are the key findings of this study?

CVA6 infection significantly elevated serum uric acid and creatinine levels in children and induced kidney injury in mice via the p38-MAPK pathway, which was alleviated by the inhibitor PD169316.

Q: What is the clinical evidence from this study?

Population: Hand, foot, and mouth disease (HFMD) / CVA6 infection (n=135). Intervention: CVA6 infection vs. Healthy controls. Primary outcome: Serum levels of uric acid (UA), creatinine (CREA), and UREA (p=<0.05).

Q: What does this research mean for the field?

Coxsackievirus A6 infection induces kidney injury through the activation of the p38-MAPK signaling pathway, and inhibiting this pathway alleviates the associated renal damage. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Q: What question did this study set out to answer?

To elucidate the clinical characteristics and molecular mechanisms of Coxsackievirus A6-induced renal injury in pediatric patients and murine models.

Tiantian Sun; Wenjie Jiang; Guangcai Duan; Dong Li; Wangquan Ji; Shuaiyin Chen; H U I Yang; Fang Wang; Shouhang Chen; Yuefei Jin; Peiyu Zhu; Mingjie Sun

doi:10.1186/s12985-026-03236-9

July 7, 2026Virology JournalOpen Access

Coxsackievirus A6 infection exacerbates kidney injury in mice through the p38-MAPK pathway

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Key result

Inhibiting p38-MAPK with PD169316 alleviates CVA6-induced kidney injury and renal dysfunction.

P<0.05
n=135

Figures

Why the study?

While renal dysfunction has been observed in some cases of severe hand, foot, and mouth disease, detailed investigations on kidney injury and molecular mechanisms remain limited.

Does PD169316 alleviate kidney injury in a mouse model of CVA6 infection?

Key Points

To elucidate the clinical characteristics and molecular mechanisms of Coxsackievirus A6-induced renal injury in pediatric patients and murine models.
Assessed serum creatinine, uric acid, and urea levels in 90 children diagnosed with Coxsackievirus A6 (CVA6) infection and 45 healthy pediatric controls.
Inoculated 10-day-old ICR mice intraperitoneally with CVA6 (10^4 TCID50/mouse) to evaluate urinary retention, renal histology, tight junction proteins, and complement deposition.
Treated CVA6-infected mice with the specific p38/MAPK inhibitor PD169316 to determine whether blocking pathway phosphorylation mitigates acute kidney injury.
Children infected with CVA6 exhibited elevated serum creatinine and uric acid levels (P<0.05), with sepsis developing in 60.53% of severe cases.
CVA6-infected mice demonstrated direct renal infection, urinary retention, glomerular basement membrane thickening, reduced tight junction protein expression, and increased serum creatinine, urea, and uric acid (P<0.05).
Pharmacological inhibition of p38 phosphorylation with PD169316 reduced renal medulla and cortex histopathological damage and mitigated severe urinary retention in infected mice.

Structured PICO

Does PD169316 alleviate kidney injury in a mouse model of CVA6 infection?

P

Population

135 children, including 90 with CVA6-induced hand, foot, and mouth disease and 45 healthy controls, were evaluated for renal function alongside a CVA6-infected mouse model.

E

Exposure

PD169316 (a specific inhibitor of p38/MAPK signaling pathway) 10 mg/kg administered via intraperitoneal injection at 3 hours post-infection and subsequently at 1, 2, and 3 days post-infection in CVA6-infected mice.

C

Comparator

Untreated CVA6-infected mice and healthy control mice.

O

Outcome

Kidney injury assessed by serum levels of uric acid (UA), creatinine (CREA), and UREA, urinary retention, and histopathological changes (glomerular atrophy, basement membrane thickening, complement deposition).surrogate

Main Result

p-value: p=<0.05

CVA6 infection exacerbates kidney injury through the p38-MAPK pathway, and pharmacological inhibition of p38 phosphorylation effectively mitigates virus-induced acute kidney injury in a mouse model.

Limitations

Lack of systematic evaluation of various anti-enterovirus agents
Limited arsenal of drugs specifically targeting inflammatory signaling pathways for preventing or treating AKI

Implication

May support p38-MAPK inhibition for CVA6 renal injury in mice; hypothesis-generating and requires clinical validation.

Abstract

Severe hand, foot, and mouth disease (HFMD) poses a risk of serious multi-organ complications in children. While renal dysfunction has been observed in some cases, detailed investigations on kidney injury and molecular mechanisms remain limited. Coxsackievirus A6 (CVA6) has emerged as a major pathogen responsible for HFMD. To reveal the underlying pathways of CVA6-associated renal injury, we enrolled 90 children diagnosed with CVA6 infection and 45 healthy children. The levels of uric acid (UA), creatinine (CREA) and UREA in the serum were measured. We found that serum levels of UA, CREA, and UREA were significantly elevated in CVA6-infected children compared to healthy children. Subsequently, a previously established mouse model of CVA6 infection was used to assess urinary retention, kidney inflammation, and histopathological changes. Consistent with the clinical findings, infected mice exhibited increased CREA, UREA, and UA levels, urinary retention, and renal inflammation. Electron microscopy revealed glomerular atrophy and basement membrane thickening in CVA6-infected mice, accompanied by reduced expression of VEGF, Occludin, and VE-cadherin. Furthermore, complement deposition was also observed in glomeruli and renal tubules. Finally, CVA6 infection significantly increased phospho-p38 levels in mouse kidneys. To investigate the role of the p38-MAPK signaling pathway in CVA6-induced renal injury, we treated the CVA6-infected mice with PD169316, a specific inhibitor of p38/MAPK signaling pathway, and observed that the kidney injury in the treated group was alleviated. Overall, our findings highlight a critical role for the p38 phosphorylation in CVA6-induced renal injury, and provide new insights into the management of severe HFMD-associated kidney complications.

Discussion

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Cite This Study

Sun et al. (2026) studied Hand, foot, and mouth disease (HFMD) / CVA6 infection (n=135). CVA6 infection vs. Healthy controls was evaluated on Serum levels of uric acid (UA), creatinine (CREA), and UREA (p=<0.05). CVA6 infection significantly elevated serum uric acid and creatinine levels in children and induced kidney injury in mice via the p38-MAPK pathway, which was alleviated by the inhibitor PD169316.

synapsesocial.com/papers/6a4debfad2ea289ef628447b https://doi.org/10.1186/s12985-026-03236-9

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Coxsackievirus A6 infection exacerbates kidney injury in mice through the p38-MAPK pathway

Figures

Key Points

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

Coxsackievirus A6 infection exacerbates kidney injury in mice through the p38-MAPK pathway

Figures

Key Points

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

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