Ultrasound Prevents Renal Ischemia-Reperfusion Injury by Stimulating the Splenic Cholinergic Anti-Inflammatory Pathway

Gigliotti, Joseph C.; Huang, Liping; Ye, Hong; Bajwa, Amandeep; Chattrabhuti, Kryt; Lee, Sangju; Klibanov, Alexander L.; Kalantari, Kambiz; Rosin, Diane L.; Okusa, Mark D.

doi:10.1681/asn.2013010084

Cited by 159 publications

(216 citation statements)

References 63 publications

(81 reference statements)

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“…12 This effect was dependent on an intact spleen and functional a7 nicotinic acetylcholine receptors (a7nAChRs), which is consistent with the hypothesis that ultrasound stimulates the splenic cholinergic anti-inflammatory pathway. As described by Tracey, 13 the cholinergic anti-inflammatory pathway is initiated via activation of the adrenergic splenic nerve and culminates with the activation of a7nAChRs.…”

supporting

confidence: 83%

“…12 Here, the same ultrasound regimen 24 hours before our standard bilateral kidney IRI (26 minutes of ischemia) reduced kidney injury as assessed by plasma creatinine (P=0.002; data not shown) and significantly (P=0.004) improved mouse survival (Figure 4).…”

Section: Protective Effect Of Ultrasound Is Dependent On the Splenic mentioning

confidence: 74%

“…12 Others have demonstrated that splenectomy before kidney IRI increased lung injury but not kidney injury. 8 It is possible that an immune modulatory function of the spleen in protecting the kidney from IRI may be missed if the injury is too severe.…”

Section: Splenectomy or Splenic Denervation Exacerbates Injury In A Smentioning

confidence: 99%

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Ultrasound Modulates the Splenic Neuroimmune Axis in Attenuating AKI

Gigliotti

Huang

Bajwa

et al. 2015

Journal of the American Society of Nephrology

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122

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We showed previously that prior exposure to a modified ultrasound regimen prevents kidney ischemiareperfusion injury (IRI) likely via the splenic cholinergic anti-inflammatory pathway (CAP) and a7 nicotinic acetylcholine receptors (a7nAChR). However, it is unclear how ultrasound stimulates the splenic CAP. Further investigating the role of the spleen in ischemic injury, we found that prior splenectomy (-7d) or chemical sympathectomy of the spleen with 6-hydroxydopamine (6OHDA; -14d) exacerbated injury after subthreshold (24-minute ischemia) IRI. 6-OHDA-induced splenic denervation also prevented ultrasoundinduced protection of kidneys from moderate (26-minute ischemia) IRI. Ultrasound-induced protection required hematopoietic but not parenchymal a7nAChRs, as shown by experiments in bone marrow chimeras generated with wild-type and a7nAChR -/-mice. Ultrasound protection was associated with reduced expression of circulating and kidney-derived cytokines. However, splenocytes isolated from mice 24 hours after ultrasound treatment released more IL-6 ex vivo in response to LPS than splenocytes from sham mice. Adoptive transfer of splenocytes from ultrasound-treated (but not sham) mice to naïve mice was sufficient to protect kidneys of recipient mice from IRI. Ultrasound treatment 24 hours before cecal ligation puncture-induced sepsis was effective in reducing plasma creatinine in this model of AKI. Thus, splenocytes of ultrasound-treated mice are capable of modulating IRI in vivo, supporting our ongoing hypothesis that a modified ultrasound regimen has therapeutic potential for AKI and other inflammatory conditions.

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supporting

confidence: 83%

Section: Protective Effect Of Ultrasound Is Dependent On the Splenic mentioning

confidence: 74%

See 1 more Smart Citation

Ultrasound Modulates the Splenic Neuroimmune Axis in Attenuating AKI

Gigliotti

Huang

Bajwa

et al. 2015

Journal of the American Society of Nephrology

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122

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“…12 Quantitative Real-Time RT-PCR Total RNA was extracted, and single-stranded cDNA was synthesized as previously described. 12,13 Primers were obtained from Integrated DNA Technologies (Coralville, IA); primer sequences for S1P1-5, 12 CXCL1, IL-6, and TNF-a, 28 and IL-1b and MCP-1 48 were as described previously. Quantitative PCR was performed using a MyIQ Single Color Real-Time PCR Detection System iCycler (Bio-Rad).…”

Section: Assessment Of Kidney Function and Histologymentioning

confidence: 99%

Sphingosine 1-Phosphate Receptor-1 Enhances Mitochondrial Function and Reduces Cisplatin-Induced Tubule Injury

Bajwa

Rosin

Chrościcki

et al. 2015

Journal of the American Society of Nephrology

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Sphingosine 1-phosphate (S1P), the natural sphingolipid ligand for a family of five G protein-coupled receptors (S1P1-S1P5Rs), regulates cell survival and lymphocyte circulation. We have shown that the pan-S1PR agonist, FTY720, attenuates kidney ischemia-reperfusion injury by directly activating S1P1 on proximal tubule (PT) cells, independent of the canonical lymphopenic effects of S1P1 activation on B and T cells. FTY720 also reduces cisplatin-induced AKI. Therefore, in this study, we used conditional PT-S1P1-null (PepckCreS1pr1 fl/fl ) and control (PepckCreS1pr1 w/wt ) mice to determine whether the protective effect of FTY720 in AKI is mediated by PT-S1P1. Cisplatin induced more renal injury in PT-S1P1-null mice than in controls. Although FTY720 produced lymphopenia in both control and PT-S1P1-null mice, it reduced injury only in control mice. Furthermore, the increase in proinflammatory cytokine (CXCL1, MCP-1, TNF-a, and IL-6) expression and infiltration of neutrophils and macrophages induced by cisplatin treatment was attenuated by FTY720 in control mice but not in PT-S1P1-null mice. Similarly, S1P1 deletion rendered cultured PT cells more susceptible to cisplatin-induced injury, whereas S1P1 overexpression protected PT cells from injury and preserved mitochondrial function. We conclude that S1P1 may have an important role in stabilizing mitochondrial function and that FTY720 administration represents a novel strategy in the prevention of cisplatin-induced AKI.

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“…12,13 In the current issue of JASN, Gigliotti et al 14 elegantly address the importance of CAP stimulation before renal IRI. In a simple but revealing first experiment, Gigliotti et al 14 show that a noninvasive ultrasound (US), which stimulates CAP through splenic afferences, efficiently prevents AKI induced by mild renal IRI in mice. The US stimulation of splenic nerves efficiently triggers the inflammatory reflex, which was shown by a significant reduction in leukocyte infiltrate (e.g., neutrophils and myeloid cells) and a reduction in IL-6 mRNA transcription.…”

Section: Cd4mentioning

confidence: 99%