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