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Abstract: PO2442

Loss of Macrophage Mitofusin 2 but Not Mitofusin 1 Suppresses Mitochondrial Biogenesis and Promotes Kidney Fibrosis

Session Information

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Bhatia, Divya, Weill Cornell Medicine, New York, New York, United States
  • Capili, Allyson M., Weill Cornell Medicine, New York, New York, United States
  • Nakahira, Kiichi, Weill Cornell Medicine, New York, New York, United States
  • Muthukumar, Thangamani, Weill Cornell Medicine, New York, New York, United States
  • Choi, Augustine MK, Weill Cornell Medicine, New York, New York, United States
  • Choi, Mary E., Weill Cornell Medicine, New York, New York, United States
Background

Mitochondrial biogenesis, dynamics (fusion/fission) and mitophagy exert critical roles in maintaining mitochondrial function and protect against oxidative stress. Macrophages are well-known to aggravate kidney injury-induced inflammation and fibrosis in the pathogenesis of chronic kidney disease (CKD). We studied the effects of macrophage mitofusins: Mfn1 and/or Mfn2 deficiency on mitochondrial biogenesis during CKD.

Methods

Myeloid-specific Mfn1 (Mfn1fl/fl,LysM-Cre+/-), Mfn2 (Mfn2fl/fl,LysM-Cre+/-), & double knockout (DKO) mice and corresponding controls were fed with control (Ctl) or adenine diet (AD) for 28-days. Kidneys,kidney macrophages,bone marrow-derived macrophages (BMDM) were analyzed by western blot,flow cytometry, immunohistochemistry. Blood urea nitrogen (BUN),creatinine were measured.

Results

Expression of mitochondrial biogenesis regulator: PGC-1α, antioxidant enzyme: superoxide dismutase-2, mitochondrial fusion proteins: Mfn1, Mfn2, and OPA-1 decreased while fission proteins: DRP-1 and phospo-DRP-1-Serine-616 increased in the kidneys after AD and BMDM after TGF-β1 treatment. Kidney macrophage superoxide levels increased after AD.However, kidney macrophages from AD-fed Mfn2fl/fl,LysM-Cre+/- and DKO mice but not Mfn1fl/fl,LysM-Cre+/- mice displayed higher superoxide & increased expression of galectin-3, TGF-β1, & CD206 than corresponding controls. In addition, Mfn2fl/fl,LysM-Cre+/- and DKO mice displayed greater collagen accumulation, and increased BUN and creatinine after AD than wild-type and Mfn1fl/fl,LysM-Cre+/- mice. Wild-type and Mfn1fl/fl,LysM-Cre+/- mice showed similar increases in collagen deposition in the kidney and worsening of kidney function after AD. BMDM from Mfn1fl/fl,LysM-Cre+/- and wild-type mice also showed similar expression of profibrotic macrophage marker, arginase-I after TGF-β1-treatment. However, TGF-β1-treated Mfn2fl/fl,LysM-Cre+/- and DKO BMDM and kidney macrophages displayed greater polarization towards profibrotic phenotype while lower expression of PGC-1α and defective mitophagy than Mfn1fl/fl,LysM-Cre+/- and wild-type macrophages.

Conclusion

Macrophage-specific deficiency of Mfn2 but not Mfn1 causes impairments in mitochondrial biogenesis and mitophagy, thereby promoting polarization towards profibrotic macrophage phenotype and kidney fibrosis.

Funding

  • Other NIH Support