Abstract: PO0404
COX-2-EP4-MafB Axis Protects Against Renal Fibrosis in Mice with Renal Ischemic Injury
Session Information
- AKI: Repair and Progression
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Pan, Yu, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Cao, Shirong, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Arroyo Ornelas, Juan Pablo, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Terker, Andrew S., Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Wang, Yinqiu, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Niu, Aolei, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Wang, Suwan, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Fan, Xiaofeng, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Harris, Raymond C., Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Zhang, Ming-Zhi, Vanderbilt University Medical Center, Nashville, Tennessee, United States
Background
The mammalian kidney is easily injured by ischemic or toxic insults but can often recover functional and structural integrity. Innate immunity is involved in both the injury and recovery processes, and its maladaptive response causes delayed recovery and development of kidney fibrosis. Cyclooxygenase 2 (COX-2) plays an essential role in antiinflammatory and tissue-reparative M2 polarization of macrophages, the major renal myeloid cells. Renal macrophage COX-2 increases after ischemic acute kidney injury (AKI). The current study investigated the role of renal macrophage COX-2 in ischemic AKI and subsequent development of fibrosis.
Methods
We developed myeloid COX-2-/- mice (CD11b-Cre; COX-2f/f), myeloid EP4-/- mice (CD11b-Cre; EP4f/f), and myeloid MafB-/- mice (LysM-Cre; MafB-/-). The animals were uninephrectomized, immediately followed by unilateral ischemia-reperfusion with renal pedicle clamping for 32 min.
Results
Following ischemic AKI, COX-2 was selectively increased in renal macrophages as indicated by colocalization with CD68, and myeloid COX-2-/- mice exhibited delayed renal recovery and increased tubulointerstitial fibrosis, in association with augmented proinflammatory cytokines in isolated renal macrophages. In bone marrow derived monocytes, PGE2 is the major COX-2-mediated arachidonic acid metabolites and acts primarily via EP4 receptors. Myeloid EP4-/- mice mimicked the effects seen with myeloid COX-2-/- mice in response to ischemic AKI. We found that myeloid EP4 activation induced expression of MafB, a master transcription factor, to upregulate antiinflammatory genes and suppress proinflammatory genes in macrophages. Selective myeloid MafB deletion recapitulated the effects seen with myeloid COX-2 or EP4 deletion, with delayed recovery and increased kidney fibrosis. Mice with myeloid deletion of COX-2, EP4, or MafB had similar impairment of renal macrophage efferocytosis.
Conclusion
These studies show that COX-2/EP4-dependent MafB expression mediates renal macrophage antiinflammatory and pro-resolving polarization and identify a previously unknown mechanism by which myeloid COX-2 inhibition exacerbates acute and chronic kidney injury, a finding that is relevant to understanding detrimental effects of NSAIDs in the setting of renal dysfunction.
Funding
- NIDDK Support