Kidney Week

Abstract: PO0197

Pulsed Ultrasound Improves Dysregulated Oxygen Metabolism and Reduces Tissue Injury in Sepsis-Associated AKI

Session Information

• AKI Mechanisms - 2
  October 22, 2020 | Location: On-Demand
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Zheng, Shuqiu, University of Virginia Health System, Charlottesville, Virginia, United States

Shuqiu Zheng,

• Sun, Naidi, University of Virginia Health System, Charlottesville, Virginia, United States

Naidi Sun,

• Rosin, Diane L., University of Virginia Health System, Charlottesville, Virginia, United States

Diane L. Rosin,

• Poudel, Nabin, University of Virginia Health System, Charlottesville, Virginia, United States

Nabin Poudel,

• Yao, Junlan, University of Virginia Health System, Charlottesville, Virginia, United States

Junlan Yao,

• Tanaka, Shinji, University of Virginia Health System, Charlottesville, Virginia, United States

Shinji Tanaka,

• Cai, Jieru, University of Virginia Health System, Charlottesville, Virginia, United States

Jieru Cai,

• Hu, Song, University of Virginia Health System, Charlottesville, Virginia, United States

Song Hu,

• Okusa, Mark D., University of Virginia Health System, Charlottesville, Virginia, United States

Mark D. Okusa,

Background

Sepsis associated-acute kidney injury (SA-AKI) results in part from oxidative stress and cytokine-induced inflammation. We showed that pulsed US (pUS) reduces inflammatory conditions and kidney injury in sepsis (PMID: 25644106). Using multi-parametric photoacoustic microscopy (PAM) we demonstrated that the imbalance between oxygen supply and oxygen demand is one of the earliest (10 min) findings in the pathogenesis of S-AKI. We tested the hypothesis that US attenuates kidney injury and improves early tissue oxygen metabolism and cellular bioenergetics.

Methods

We used PAM imaging to assay the change of renal blood oxygen saturation (sO₂), peritubular capillary (PC) blood flow (BF) and the metabolic rate of oxygen (MRO₂) in saline- and LPS-treated mice and mice pretreated with US 24 hr before LPS (as described PMID: 25644106). Mice received a single injection of LPS (5 mg/kg, i.p.), and oxygen consumption and blood flow were measured 10-80 min later by PAM imaging with an image penetration depth of up to 200 µm, and MRO₂ was calculated. Additional animals were treated with LPS and euthanized at increasing time intervals for measurement of blood creatinine and injury and inflammatory biochemical markers.

Results

PAM imaging revealed heterogeneous cortical regions of LPS- induced markedly enhanced oxygen consumption and MRO₂. Pretreatment with US reversed the early renal sO₂ decline observed 30-80 min after LPS and reversed the cortical regions of increased MRO₂. pUS prevented the overall reduction of PCBF. LPS-induced AKI, confirmed by increased plasma creatinine, mRNA expression of kidney injury marker Kim1 and Ngal 12-24 hr after LPS, and acute tubular necrosis (by H&E staining), was attenuated by US pretreatment. pUS reduced Kim1 expression in the brush border membrane of proximal tubules in cortex and medulla. pUS attenuated the increase in IL-6 and IFN-γ, but not TNF-α, mRNA expression.

Conclusion

Our results demonstrate that pUS reverses kidney MRO₂, improves oxygen metabolism and reduces proinflammatory cytokines in SA-AKI. These results provide insight into the mechanisms of kidney tissue protection by US in AKI.

Funding

• NIDDK Support