Mitophagy-dependent macrophage reprogramming protects against kidney fibrosis

被引：151

作者：

Bhatia, Divya ^{[1
]}

Chung, Kuei-Pin ^{[2
,3
]}

Nakahira, Kiichi ^{[2
]}

Patino, Edwin ^{[1
]}

Rice, Michelle C. ^{[1
]}

Torres, Lisa K. ^{[2
]}

Muthukumar, Thangamani ^{[1
,4
]}

Choi, Augustine M. K. ^{[2
,4
]}

Akchurin, Oleh M. ^{[4
,5
]}

Choi, Mary E. ^{[1
,4
]}

机构：

[1] Weill Cornell Med, Div Nephrol & Hypertens, Joan & Sanford I Weill Dept Med, 525 East 68th St,Box 3, New York, NY 10065 USA

[2] Weill Cornell Med, Div Pulm & Crit Care Med, Joan & Sanford I Weill Dept Med, 1300 York Ave,Suite F-113 Box 83, New York, NY 10065 USA

[3] Natl Taiwan Univ Hosp, Taipei, Taiwan

[4] NewYork Presbyterian Hosp, New York, NY USA

[5] Weill Cornell Med, Div Pediat Nephrol, Dept Pediat, New York, NY USA

来源：

JCI INSIGHT | 2019年 / 4卷 / 23期

关键词：

RENAL FIBROSIS; PATHOPHYSIOLOGICAL ROLES; MITOFUSIN; TGF-BETA; AUTOPHAGY; MECHANISMS; PARKIN; MITOCHONDRIA; INFLAMMATION; EXPRESSION;

D O I：

10.1172/jci.insight.132826

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Mitophagy, by maintaining mitochondrial quality control, plays a key role in maintaining kidney function and is impaired in pathologic states. Macrophages are well known for their pathogenic role in kidney fibrosis. Here, we report that PINK1/Parkin-mediated mitophagy in macrophages is compromised in experimental and human kidney fibrosis. We demonstrate downregulation of mitophagy regulators mitofusin-2 (MFN2) and Parkin downstream of PINK1 in kidney fibrosis. Loss of either Pink1 or Prkn promoted renal extracellular matrix accumulation and frequency of profibrotic/M2 macrophages. Pink1(-/-) or Prkn(-/-) BM-derived macrophages (BMDMs) showed enhanced expression of rictor. Mitochondria from TGF-beta 1-treated Pink1(-/-) BMDMs exhibited increased superoxide levels, along with reduced respiration and ATP production. In addition, mitophagy in macrophages involves PINK1-mediated phosphorylation of downstream MFN2, MFN2-facilitated recruitment of Parkin to damaged mitochondria, and macrophage-specific deletion of Mfn2 aggravates kidney fibrosis. Moreover, mitophagy regulators were downregulated in human CKD kidney and TGF-beta 1-treated human renal macrophages, whereas Mdivi1 treatment suppressed mitophagy mediators and promoted fibrotic response. Taken together, our study is the first to our knowledge to demonstrate that macrophage mitophagy plays a protective role against kidney fibrosis via regulating the PINK1/MFN2/Parkin-mediated pathway.

引用

页数：20

共 52 条

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