Abstract: SA-PO802
Macrophage-Derived miR-155-Containing Exosomes Promotes Angiotensin-II Induced Senescence and Oxidative Stress in Proximal Tubular Cells
Session Information
- Molecular Mechanisms of CKD - III
October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 1903 CKD (Non-Dialysis): Mechanisms
Authors
- Wang, Bin, Zhong Da Hospital, Southeast University, Nanjing, China
- Ji, Jialing, Nanjing Medical University, Nanjing, Jiangsu, China
- Liu, Bi-Cheng, Zhong Da Hospital, Southeast University, Nanjing, China
Background
The activation of the renin-angiotensin (Ang)-aldosterone system (RAAS) is a major hallmark in the development and progression of organ damage in chronic kidney disease (CKD). Here, we examined the role of macrophage-derived miR-155-containing exosomes in regulating oxidative stress and senescence in Ang-II induced PTCs both in vivo and in vitro.
Methods
CKD mice model: An osmotic minipump was implanted subcutaneously to infuse Ang-II for 4 weeks after a right uninephrectomy or sham operation in wild type or miR-155-deficient mice. Macrophage-derived miR-155-containing exosomes were infused in miR-155-deficient mice through tail injection. In vitro, primary cultured PTCs were treated with Ang-II (10-7M) in the presence or absence of macrophage-derived miR-155-containing exosomes or miR-155 inhibitor. Finally, kidney samples and cultured PTCs in various groups as indicated above were analyzed for markers of senescence and oxidative stress.
Results
Our study revealed that miR-155 expression, the number of infiltrated macrophages, and oxidative stress and senescence were substantially increased in PTCs in Ang-II infused mice relative to the control group. Ang-II infused miR-155-deficient mice display attenuated senescence and mild oxidative stress compared that in wild type mice. Conversely, macrophage-derived miR-155-containing exosomes enhanced oxidative stress and senescence in Ang-II infused miR-155-deficient mice. Interestedly, pri-miR-155 was only expressed in macrophages, but not in PTCs, and macrophage-derived miR-155-containing exosomes can be transferred into PTCs. Hence, it is not strange that blocking exosome secretion with GW6849 attenuated oxidative stress and senescence in Ang-II infused wild type mice. Additionally, we found that miR-155 inhibitor abrogated oxidative stress and senescence in PTCs by directly down-regulating FoxO3a expression.
Conclusion
Taken together, our results demonstrated that infiltrated macrophages secreted miR-155-enriched exosomes and promoted oxidative stress and senescence by directly targeting FoxO3a in Ang-II infused PTCs injury.
Funding
- Government Support - Non-U.S.