Kidney Week

Abstract: SA-OR070

Macrophage Mitophagy Deficiency Promotes Experimental and Human Kidney Fibrosis

Session Information

• Mechanisms of Kidney and Cardiovascular Damage in CKD
  November 09, 2019 | Location: 206, Walter E. Washington Convention Center
  Abstract Time: 04:54 PM - 05:06 PM

Category: CKD (Non-Dialysis)

• 2103 CKD (Non-Dialysis): Mechanisms

Authors

• Bhatia, Divya, Weill Cornell Medicine, New York, New York, United States

Divya Bhatia, PhD



Dr. Divya Bhatia is a Postdoctoral Associate at Weill Cornell Medicine, New York. She completed her Ph.D. from All India Institute of Medical Sciences, India and a research fellowship from the University of Bristol, United Kingdom. She has been invited as a speaker to present her research work by the American Society of Nephrology in the Kidney Week meetings - 2017, 2018, and 2019, and the International Pediatric Nephrology Association (IPNA-2016). She regularly peer-reviews for several journals including Frontiers in Medicine (Nephrology), Scientific Reports, Aging, Oncotarget, PeerJ, and American Journal of Nephrology. She is a member of the editorial board of CPQ Medicine and Journal of Nephrology Advances and reviewer board of the Current Trends in Inflammation Research. She is committed to research on kidney diseases from the past eight years. Her current area of interest is to explore the signaling pathways of mitochondrial autophagy of macrophages and proximal tubules during kidney fibrosis. She is a member of the American Society of Nephrology, American Association for the Advancement of Science, The New York Academy of Sciences, and former Associate Member of the American Association of Immunology.

• Chung, Kuei-Pin, Weill Cornell Medicine, New York, United States

Kuei-Pin Chung,

• Nakahira, Kiichi, Weill Cornell Medicine, New York, New York, United States

Kiichi Nakahira,

• Patino, Edwin, Weill Cornell Medicine, New York, New York, United States

Edwin Patino,

• Rice, Michelle C., Weill Cornell Medicine, New York, New York, United States

Michelle C. Rice,

• Torres, Lisa K., Weill Cornell Medicine, New York, New York, United States

Lisa K. Torres,

• Muthukumar, Thangamani, Weill Cornell Medicine, New York, New York, United States

Thangamani Muthukumar,

• Choi, Augustine MK, Weill Cornell Medicine, New York, New York, United States

Augustine MK Choi,

• Akchurin, Oleh M., Weill Cornell Medicine, New York, New York, United States

Oleh M. Akchurin,

• Choi, Mary E., Weill Cornell Medicine, New York, New York, United States

Mary E. Choi,

Background

Mitochondrial quality control by mitophagy is critical for normal kidney function. We examined the role of PINK1, Mitofusin 2 (MFN2) and Parkin-mediated mitophagy in macrophage-induced kidney fibrosis, using experimental models of adenine diet (AD) or unilateral ureteral obstruction (UUO) and in human kidney fibrosis.

Methods

Kidney fibrosis in Pink1^-/- or Prkn^-/- mice was induced by AD or UUO. Role of MFN2 was studied using LysM-Cre^+/-Mfn2^fl/fl mice. Kidney tissues and primary macrophages were analyzed by flow cytometry, confocal and electron microscopy, qPCR, western blot, ELISA, and MitoStress test. PBMCs, plasma and kidney biopsies from patients with severe-CKD (GFR<30 ml/min/1.73m²,n=15) or biopsy-proven interstitial fibrosis & tubular atrophy (IFTA,n=6) were compared to patients with mild/moderate-CKD (GFR>30,n=8) or controls (no CKD,n=9).

Results

Expression of PINK1, MFN2, and Parkin was decreased in kidneys and renal macrophages after AD or UUO, as well as in TGF-β1-treated bone-marrow-derived macrophages (BMDMs), human renal macrophages, and THP-1-cells. Kidneys from Pink1^-/- and Prkn^-/- mice showed higher fibronectin, collagen-I, TGF-β1, galectin-3, and arginase-I after AD or UUO vs corresponding wild-type mice. Renal macrophages from AD-fed Pink1^-/-mice had a higher number of abnormal mitochondria. Ly6C^lowCD11b+, F4.80+CD206+ cells and CCL2 levels were increased in blood and kidneys from Pink1^-/- and Prkn^-/-mice after AD or UUO. Mitochondria from TGF-β1-treated Pink1^-/- BMDMs showed lower respiration, higher mitochondrial ROS (mROS), and reduced colocalization with LC3. Mitophagy inhibition by Pink1-siRNA or Mdivi-1 resulted in decreased phosphorylation of downstream MFN2 and increased fibrotic response by human macrophages. LysM-Cre^+/-Mfn2^fl/fl macrophage mitochondria displayed lower recruitment of Parkin and mitophagy. Plasma, PBMCs, and kidney biopsies from patients with severe-CKD and IFTA showed higher CCL2 and mROS, and lower PINK1, MFN2 and PRKN expression.

Conclusion

Our study is the first to demonstrate that deficiency of PINK1/MFN2/PRKN-mediated mitophagy promotes macrophage-induced oxidative stress and fibrotic response, and is associated with human kidney fibrosis. Therapeutically targeting macrophage mitophagy pathway may protect against kidney fibrosis.

Funding

• NIDDK Support