Abstract / Summary
Abstract Background Sepsis-associated acute kidney injury (S-AKI) is frequently accompanied by albuminuria, highlighting the need to protect the glomerular filtration barrier during systemic inflammation. The cholinergic anti-inflammatory pathway (CAP) limits inflammatory responses through α7 nicotinic acetylcholine receptors (α7nAChR), but CAP-based renoprotection has been mainly studied in immune and tubular compartments. Here we tested whether α7nAChR activation directly protects podocytes in S-AKI. Results In an LPS-induced mouse model, pretreatment with the α7nAChR agonist GTS-21 improved renal function, reduced albuminuria, preserved podocyte ultrastructure, and maintained nephrin, podocin, synaptopodin, and podocalyxin; it also partially restored ZO-1 organization in glomerular and tubular compartments. Chrna7 signals were broadly distributed within glomeruli, with partial colocalization with the podocyte marker podocin; α7nAChR expression was also detected in cultured podocytes. Using podocyte-specific Chrna7 knockout mice, we show that podocyte Chrna7 deletion attenuated GTS-21–mediated reductions in albuminuria and blunted preservation of podocyte markers and glomerular ZO-1, indicating that podocyte α7nAChR substantially contributes to the glomerular protective effects of α7nAChR activation. In cultured podocytes, GTS-21 preserved synaptopodin and improved ZO-1 continuity under LPS challenge. Transcriptomic analysis and time-course studies revealed that α7nAChR activation blunted LPS-induced NF-κB signaling, including p65 nuclear translocation, phosphorylation, and target gene expression. Conclusions Together, these findings identify podocytes as a direct CAP/α7 target and support α7 activation as a multi-compartment strategy to preserve glomerular barrier integrity in septic kidney injury.