Abstract: SA-PO803
Macrophage Chemoattractant Protein-1 (MCP-1) Promotes Renal Fibrosis in AKI-to-CKD Transition
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
- Xu, Leyuan, Yale University School of Medicine, New Haven, Connecticut, United States
- Cantley, Lloyd G., Yale University School of Medicine, New Haven, Connecticut, United States
Background
Acute kidney injury (AKI) significantly increases the risk of developing progressive kidney fibrosis and chronic kidney disease (CKD). Macrophages play complex roles in AKI, with proinflammatory macrophages initially serving for clearance of apoptotic cells/debris after injury, followed by reparative macrophages promoting tubule repair. Using a CKD model of unilateral ischemia-reperfusion (U-IRI) in which the injured kidney undergoes fibrosis and atrophy rather than effective repair, we recently showed that macrophages downregulate reparative activation and transition to a profibrotic phenotype by day 14 after injury. In this study, we investigated the mechanism by which macrophages become profibrotic during the AKI-to-CKD transition.
Methods
Male wild-type or Ccr2-/- mice were subjected to warm U-IRI (27 min). Serum KIM1 level on day 1 after U-IRI was used to define the degree of initial injury. The injured kidney was removed on day 14 or 30 after U-IRI. Renal cells were flow sorted on day 14 to define the macrophage homing signals. Renal fibrosis was assessed on day 30 by Sirius red staining, qPCR and Western blotting for Col1a1, Col3a1 and Fn1. Macrophage accumulation was assessed by IHC for F4/80 and qPCR for Cd68. Interstitial inflammation was assessed by qPCR for Tnfa.
Results
Failure of kidney repair by day 14 after U-IRI led to sustained high expression of macrophage chemoattractant protein-1 (Mcp1) in the injured kidney compared to the contralateral control kidney (53-fold increase, n=10, p<0.001). CD45+F4/80+ macrophages and CD45+CD11c+F4/80- dendritic cells were the major cellular sources of this late, persistent Mcp1 expression (34- and 5-fold increase compared to renal cells and CD45+CD11c-F4/80- T cells/PMNs), while all bone marrow derived CD45+ cells expressed high levels of the Mcp1 receptor Ccr2. Injured kidneys from Ccr2-/- mice showed ~30% less profibrotic macrophage accumulation, interstitial fibrosis and inflammation in comparison to the wild-type control mice (n=5, p<0.01). Furthermore, administration of a CCR2 inhibitor (RS102895, 5 mg/kg, every 12 h) to wild-type mice for 7 days beginning 7 days after U-IRI replicated these results (n=8, p<0.05).
Conclusion
Our data showed that MCP-1 may serve as an autocrine and/or paracrine factor for profibrotic macrophage accumulation, leading to increased interstitial fibrosis during the AKI-to-CKD transition.
Funding
- NIDDK Support