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Kidney Week

Abstract: PO0591

Conditional Deletion of Myeloid-Specific Mitofusin 2 Promotes Kidney Fibrosis

Session Information

  • CKD Mechanisms - 1
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

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
  • Akchurin, Oleh M., Weill Cornell Medicine, New York, New York, United States
  • Choi, Mary E., Weill Cornell Medicine, New York, New York, United States
Background

Mitochondrial dysfunction is implicated in the pathogenesis of CKD. Mitochondrial dynamics regulate macrophage mitochondrial stress responses; we hypothesize that their impairment leads to kidney fibrosis. We determined the role of myeloid-specific mitochondrial fusion proteins (MFN)1 and MFN2 in PINK1-mediated mitophagy in experimental and human kidney fibrosis.

Methods

Pink1-/-, myeloid-specific Mfn1 (LysM-Cre+/−Mfn1fl/fl), Mfn2 (LysM-Cre+/−Mfn2fl/fl) null mice and corresponding controls were subjected to unilateral ureteral obstruction (UUO,7-days) or adenine diet (AD,28-days). Kidneys,renal macrophages (RMs),bone marrow-derived macrophages (BMDMs),PBMCs, and plasma were analyzed by western blot,qPCR,Mito stress test,ELISA,immunohistochemistry,flow cytometry,confocal and electron microscopy. Patients with renal biopsy-proven interstitial fibrosis & tubular atrophy (IFTA,n=6) and severe-CKD (GFR<30 ml/min,n=15) were compared to controls (no IFTA,n=9) and mild/moderate-CKD (GFR>30 ml/min,n=8).

Results

MFN1 and MFN2 expression decreased in kidneys after UUO or AD, and BMDMs after TGF-β1 treatment. AD-fed LysM-Cre+/−Mfn2fl/fl but not LysM-Cre+/−Mfn1fl/fl mice displayed increased renal expression of CD11b+F4/80+ macrophages than AD-fed controls. Increases in fibronectin,CD206,galectin-3, and TGF-β1 expression in the kidneys and RMs were higher in AD-fed LysM-Cre+/−Mfn2fl/fl mice than AD-fed controls. TGF-β1-induced inhibition of mitophagy and increases in mitochondrial mass, size, and superoxide levels were greater in LysM-Cre+/−Mfn2fl/fl RMs and BMDMs than LysM-Cre+/−Mfn1fl/fl and controls. The reduction in colocalization of MFN2 but not MFN1 with renal mitochondria after UUO was higher in Pink1-/- mice. PBMCs from patients with severe-CKD showed higher superoxide levels and lower MFN2 expression than mild/moderate-CKD. IFTA was associated with lower renal expression of MFN1 and MFN2 and higher circulating CCL2 levels than controls. Decreased MFN2 and PINK1 expression in TGF-β1-treated human RMs was associated with increased fibrotic response.

Conclusion

This study is the first to suggest that myeloid-specific MFN2 but not MFN1 by regulating renal macrophage mitochondrial biogenesis and mitophagy prevents fibrosis. Mitophagy inducers may attenuate macrophage superoxide production and progression of kidney fibrosis.

Funding

  • NIDDK Support