LPS誘導的敗血症相關急性腎損傷中腎臟第二型化學感受器之神經調控

劉珮渝^1,3、鄭劍廷¹、林威佑^1,2、林三齊³

¹國立臺灣師範大學生命科學院；²衛生福利部臺北醫院泌尿科；

³衛生福利部基隆醫院腎臟科

The neural mechanisms of renal R2 chemoreceptor in LPS-induced SA-AKI

Pei-Yu Liu¹、Chiang-Ting Chien¹、Wei-Yu Lin^1,2、San-Chi Lin³

¹Department of Life Science, National Taiwan Normal University, Taipei, Taiwan；

²Department of Urology,Taipei Hospital, Ministry of Health and Welfare, New Taipei City, Taiwan；

³Department of Kidney,Keelung Hospital, Ministry of Health and Welfare, Keelung City, Taiwan

Purpose:

Sepsis-associated acute kidney injury（SA-AKI）is a complex disease with high morbidity and mortality, associated with excessive and dysregulated immune response. Renal afferent sensory nerves can perceive surrounding information through mechanoreceptors and chemoreceptors, to participate in neuroimmunologic regulation. However, their mechanisms have not been clearly understood in the disease of SA-AKI. The concentration of extracellular adenosine triphosphate （eATP）was found to be significantly increased in sepsis. After binding to purinergic receptors, it can activate the inflammation and oxidative stress pathway and acts as a neurotransmitter. Therefore, eATP may be a key molecule involved in the regulation of neural activity in LPS-induced SA-AKI. In this study, we aimed to understand the involvement of renal nerves in SA-AKI.

Materials and Methods:

Female Wistar rats were used in this research. A single intravenous injection of LPS (50 mg/kg) was used to induce SA-AKI. We used electrophysiology and single-unit isolation to measure the changes of renal nerve activity and identify the type of renal sensory receptor which has been affected. We conducted the measurement of renal arterial blood flow, eATP concentration, immunofluorescence staining, and P2X receptor antagonist administration to discover the possible mechanism resulting in renal nerve activity alteration. Finally, the techniques of western blot and cytokine microarrays were used to explore the underlying mechanism after renal sensory receptors stimulation.

Results:

Our results showed that LPS-induced sepsis can activate the renal efferent sympathetic nerve fibers and the type 2 of chemoreceptor (CR2). In addition, the level of renal arterial blood flow was reduced. Moreover, the increase of eATP was detected in plasma, urine, and NRK52E cells’ conditioned medium, and CR2 was activated by backflow of ATP solution from the ureter. Therefore, we speculated that LPS may cause renal hypoxia/ischemia by reducing renal perfusion pressure, causing injured tissue to release ATP. eATP acts as a neurotransmitter to stimulate CR2, leading to an increase in the activity of renal afferent nerves. It is expected that the administration of ATP receptor antagonists can inhibit the activation of CR2 caused by LPS, confirming that eATP can affect CR2 activity by binding to P2XR. In addition, the activation of CR2 may be involved in the renal dysfunction.

Conclusion:

In this study, we aimed to understand the response and underlying mechanisms of renal nerves in LPS-induced SA-AKI. Our results suggest that LPS may increase the CR2 renal afferent nerves activities through ATP-P2X7R pathway.