Abstract: TH-PO0127
Optogenetic Activation of Renal Sympathetic Nerves Protects Against AKI by Modulating Mitochondrial Metabolism and Redox Stress: Insights from Single-Cell Transcriptomics
Session Information
- AKI: Mechanisms - 1
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Umene, Ryusuke, Department of Physiology of Visceral Function and Body Fluid, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
- Washimine, Norito, Department of Physiology of Visceral Function and Body Fluid, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
- Wu, Chia-Hsien, Department of Physiology of Visceral Function and Body Fluid, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
- Nakamura, Yasuna, Department of Physiology of Visceral Function and Body Fluid, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
- Nishino, Tomoya, Department of Nephrology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
- Inoue, Tsuyoshi, Department of Physiology of Visceral Function and Body Fluid, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
Background
The kidney is densely innervated by sympathetic nerves, and adrenergic receptors are abundantly expressed in renal tubules, the primary injury site in acute kidney injury (AKI), suggesting close involvement of sympathetic signaling in AKI pathogenesis. However, the cellular and metabolic protective effects of renal sympathetic modulation remain largely unexplored.
Methods
We used DbH-Cre/ChR2 mice, which express channelrhodopsin-2 specifically in sympathetic neurons, enabling selective activation by blue light. Optical fibers were implanted around the renal artery to deliver light. In vivo extracellular recordings confirmed light-evoked action potentials in renal sympathetic nerves, validating functional stimulation. AKI was induced by bilateral ischaemia-reperfusion injury 24 hours after optogenetic stimulation. Arterial blood pressure and renal blood flow were continuously monitored. Single-cell RNA-seq of kidneys was performed to assess transcriptomic changes. In vitro hypoxia experiments using HK-2 cells were conducted to evaluate norepinephrine’s effects on NGAL expression, NAD+/NADH assay, and extracellular flux analysis.
Results
Optogenetic stimulation significantly attenuated elevations in serum creatinine and renal NGAL expression and reduced tubular injury. No changes in systemic blood pressure or renal perfusion were observed, indicating protection independent of hemodynamics. Single-cell RNA-seq showed upregulation of mitochondrial respiratory chain genes, especially NADH dehydrogenase, in proximal tubules. In vitro, norepinephrine suppressed hypoxia-induced NGAL expression, increased the NAD+/NADH ratio, and enhanced mitochondrial proton leak in HK-2 cells. Renal tissues from stimulated mice showed reduced mitochondrial reactive oxygen species (ROS).
Conclusion
Renal sympathetic stimulation using optogenetics protects against AKI by enhancing mitochondrial respiratory flexibility in tubular cells. Sympathetic activation appears to sacrifice partially ATP synthesis to increase mitochondrial flexibility, thereby providing protection against ROS-induced cytotoxicity. This mitochondria-targeted strategy offers a promising avenue for non-pharmacological kidney protection.