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Abstract: SA-PO1005

Myeloid-Specific Mitochondrial Fusion Proteins MFN1 and MFN2 Regulate Lung Injury Associated With CKD

Session Information

  • CKD: Pathobiology - II
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2203 CKD (Non-Dialysis): Mechanisms

Authors

  • Bhatia, Divya, Weill Cornell Medicine, NY, New York, United States
  • Plataki, Maria, Weill Cornell Medicine, NY, New York, United States
  • Choi, Mary E., Weill Cornell Medicine, NY, New York, United States
Background

Association of chronic kidney disease (CKD) and lung injury is under-recognized. Studies suggest increased prevalence of CKD in idiopathic pulmonary fibrosis (IPF) patients associates with worse survival than patients without CKD. We sought to understand mechanistic link between kidney and lung injury and role of macrophage mitochondrial fusion proteins, mitofusin (MFN)1 and MFN2.

Methods

Myeloid-specific Mfn1 (Mfn1fl/fl,LysM-Cre+/-), Mfn2 (Mfn2fl/fl,LysM-Cre+/-), or Mfn1/Mfn2 double knockout (DKO) and corresponding flox/flox LysM-Cre-/- wild-type (WT) mice were subjected to unilateral ureteral obstruction (7-days) or sham surgery, or adenine (AD) or control (Ctl) diet (4 or 8-weeks). Lungs, bronchoalveolar lavage (BAL), and blood were collected and analyzed by flow cytometry and western blot.

Results

Pro-inflammatory monocytes (Ly6C+CD11b+), macrophages (infiltrated: CD11b+ CD64+SiglecF-; resident: SiglecF+CD11b-), and fibrotic response (arginase-I, galectin-3, YM-1, CD86, fibronectin,collagen-I) increased while anti-inflammatory monocytes (Ly6C-CD11b+) and MFN1 and MFN2 expression decreased in lungs from WT mice after UUO or AD than sham or Ctl respectively. Circulating pro-inflammatory (Ly6C+CCR2+) and profibrotic (galectin-3+,TGF-β+) markers on monocytes but not on other (CD11b-) cells increased in WT mice after AD than Ctl. AD-fed WT but not Mfn2fl/fl,LysM-Cre+/- or DKO mice displayed an increase in infiltration of pro-inflammatory monocytes in lungs than Ctl. Mfn2fl/fl,LysM-Cre+/- mice displayed lower expression of fibrotic markers while higher total MFN2 expression in lungs during CKD than WT mice. Alveolar type II epithelial cells (AEC II, EpCAM+CD45-) from AD-fed Mfn2fl/fl,LysM-Cre+/- mice had a higher expression of MFN2 than AD-fed WT mice. Mfn1fl/fl,LysM-Cre+/- mice also displayed lower expression of galectin-3 and exhibited a compensatory increase in MFN1 expression in lungs than WT mice after AD. BAL from WT but not DKO mice displayed an increase in pro-inflammatory monocytes after AD than Ctl.

Conclusion

Pro-inflammatory monocytes/macrophages and fibrotic response in lungs were increased in experimental CKD in WT mice, with increases in circulating pro-inflammatory and profibrotic monocytes. Myeloid-specific Mfn1 or Mfn2-deficiency resulted in attenuation, potentially mediated by compensatory induction of MFN1 and MFN2 expression in AEC II.

Funding

  • Other NIH Support