Abstract: SA-PO0281
Tubular β2-Adrenergic Receptor-ZIP10-Metallothionein Signaling Mediates Renal Sympathetic Nerve-Induced Protection Against Septic AKI
Session Information
- AKI: Mechanisms - Cell Signaling
October 24, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Shimoyama, Kotaro, Nagasaki Daigaku Daigakuin Ishiyakugaku Sogo Kenkyuka, Nagasaki, Nagasaki Prefecture, Japan
- Umene, Ryusuke, Nagasaki Daigaku Daigakuin Ishiyakugaku Sogo Kenkyuka, Nagasaki, Nagasaki Prefecture, Japan
- Wu, Chia-Hsien, Nagasaki Daigaku Daigakuin Ishiyakugaku Sogo Kenkyuka, Nagasaki, Nagasaki Prefecture, Japan
- Nakamura, Yasuna, Nagasaki Daigaku Daigakuin Ishiyakugaku Sogo Kenkyuka, Nagasaki, Nagasaki Prefecture, Japan
- Inoue, Tsuyoshi, Nagasaki Daigaku Daigakuin Ishiyakugaku Sogo Kenkyuka, Nagasaki, Nagasaki Prefecture, Japan
Background
The kidney is densely innervated by sympathetic nerves, which are classically recognized for regulating renal vascular tone and hemodynamics. However, adrenergic receptors are also expressed in renal tubular epithelial cells, suggesting that sympathetic signals may directly modulate tubular function. The physiological significance of this neuro-tubular communication remains poorly understood. In this study, we investigated whether renal sympathetic nerve activation protects against septic acute kidney injury (AKI) by acting directly on renal tubular cells.
Methods
To selectively activate renal sympathetic nerves, we used an optogenetic approach. Dopamine β-hydroxylase-Cre; channelrhodopsin-2 mice (DbH-Cre:ChR2), in which blue light-sensitive channelrhodopsin-2 is expressed in sympathetic neurons, were subjected to renal sympathetic nerve stimulation by applying blue light to the renal hilum for 5 minutes at 20 Hz. Septic AKI was induced by intraperitoneal injection of lipopolysaccharide (LPS, 5 mg/kg), and renal injury was assessed 24 hours later.
Results
Optogenetic renal sympathetic nerve activation reduced plasma creatinine and BUN 24 hours after LPS administration, decreased renal Ngal and Kim-1 expression, and attenuated Kim-1-positive tubular injury. β2-adrenergic receptor was expressed in renal tubular epithelial cells. β2-adrenergic receptor agonist treatment reproduced the protective effect, whereas proximal tubule-specific β2-adrenergic receptor deletion exacerbated LPS-induced AKI. In HK-2 cells, β2-adrenergic receptor stimulation reduced LPS-induced NGAL expression. RNA sequencing showed upregulation of antioxidant and zinc homeostasis pathways, including metallothionein 1 (MT1). MT1 overexpression reduced reactive oxygen species and tubular injury. β2-adrenergic receptor activation also increased ZIP10/SLC39A10 expression and intracellular zinc influx, suggesting a ZIP10–zinc–MT1 pathway downstream of tubular β2-adrenergic receptor signaling.
Conclusion
Renal sympathetic nerve activation protects against septic AKI through direct signaling to tubular β2-adrenergic receptors. This pathway enhances ZIP10-mediated zinc influx and induces the antioxidant factor MT1, thereby reducing oxidative stress and tubular injury.
Funding
- Government Support – Non-U.S.