Alpha-7 nicotinic acetylcholine receptor activation preserves podocyte integrity during sepsis-associated kidney injury
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.
Related
- The mode of action of neonicotinoids and related compounds on insect neuronal nicotinic acetylcholine receptors highlights complex intracellular calcium mechanisms
- Mass photometry and its expanding role in membrane protein research: The Torpedo marmorata nicotinic acetylcholine receptor as case study
- Cryo-EM Structure of a Triazole alpha-Conotoxin GI Mimetic Bound to the Muscle-Type Nicotinic Acetylcholine Receptor
- A Review of the Roles of Calcium Signaling and Homeostasis in Nicotine Addiction: A Mechanistic Hypothesis Involving ATP2B2/PMCA2 and α7-Nicotinic Acetylcholine Receptors
- Dysregulation of Expression of Nicotinic Acetylcholine Receptors and Ly6/uPAR Proteins in the Cingulate Gyrus of the Cerebral Cortex of Patients with Alzheimer's Disease.
BibTeX
@article{yang2026alpha7,
title = {{Alpha-7 nicotinic acetylcholine receptor activation preserves podocyte integrity during sepsis-associated kidney injury}},
author = {Aobing Yang and Chia-Hsien Wu and Kotaro Shimoyama and Ryoko Yamamoto and Ryusuke Umene and Yasuna Nakamura and Yuan Zhang and Tsuyoshi Inoue},
journal = {BMC Biology},
year = {2026},
month = oct,
doi = {10.1186/s12915-026-02758-6},
url = {https://link.springer.com/10.1186/s12915-026-02758-6},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Alpha-7 nicotinic acetylcholine receptor activation preserves podocyte integrity during sepsis-associated kidney injury
AU - Aobing Yang
AU - Chia-Hsien Wu
AU - Kotaro Shimoyama
AU - Ryoko Yamamoto
AU - Ryusuke Umene
AU - Yasuna Nakamura
AU - Yuan Zhang
AU - Tsuyoshi Inoue
PY - 2026
DA - 2026/10/08
JO - BMC Biology
DO - 10.1186/s12915-026-02758-6
UR - https://link.springer.com/10.1186/s12915-026-02758-6
AB - 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.
SN - 1741-7007
ER -