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

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.