Inhibition of MTOR Disrupts Autophagic Flux in Podocytes

被引：149

作者：

Cina, Davide P. ^{[1
]}

Onay, Tuncer ^{[1
]}

Paltoo, Aarti ^{[1
]}

Li, Chengjin ^{[1
]}

Maezawa, Yoshiro ^{[1
]}

De Arteaga, Javier ^{[2
]}

Jurisicova, Andrea ^{[1
]}

Quaggin, Susan E. ^{[1
,3
,4
]}

机构：

[1] Univ Toronto, Samuel Lunenfeld Res Inst, Mt Sinai Hosp, Toronto, ON M5T 3L9, Canada

[2] Catholic Univ, Cordoba, Argentina

[3] Univ Toronto, Univ Hlth Network, Dept Med, Toronto, ON M5T 3L9, Canada

[4] Univ Toronto, St Michaels Hosp, Div Nephrol, Toronto, ON M5T 3L9, Canada

来源：

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY | 2012年 / 23卷 / 03期

基金：

加拿大健康研究院;

关键词：

FOCAL SEGMENTAL GLOMERULOSCLEROSIS; POLYCYSTIC KIDNEY-DISEASE; ENDOTHELIAL GROWTH-FACTOR; THROMBOTIC MICROANGIOPATHY; DIABETIC-NEPHROPATHY; ACTIN CYTOSKELETON; SIROLIMUS; EXPRESSION; MICE; ACTIVATION;

D O I：

10.1681/ASN.2011070690

中图分类号：

R5 [内科学]; R69 [泌尿科学（泌尿生殖系疾病）];

学科分类号：

1002 ; 100201 ;

摘要：

Inhibitors of the mammalian target of rapamycin (MTOR) belong to a family of drugs with potent immunosuppressive, antiangiogenic, and antiproliferative properties. De novo or worsening proteinuria can occur during treatment with these agents, but the mechanism by which this occurs is unknown. We generated and characterized mice carrying a podocyte-selective knockout of the Mtor gene. Although Mtor was dispensable in developing podocytes, these mice developed proteinuria at 3 weeks and end stage renal failure by 5 weeks after birth. Podocytes from these mice exhibited an accumulation of the autophagosome marker LC3 (rat microtubule-associated protein 1 light chain 3), autophagosomes, autophagolysosomal vesicles, and damaged mitochondria. Similarly, human podocytes treated with the MTOR inhibitor rapamycin accumulated autophagosomes and autophagolysosomes. Taken together, these results suggest that disruption of the autophagic pathway may play a role in the pathogenesis of proteinuria in patients treated with MTOR inhibitors.

引用

页码：412 / 420

页数：9

共 40 条

[11] The Pharmacology of mTOR Inhibition [J].

Guertin, David A. ;

Sabatini, David M. .

SCIENCE SIGNALING, 2009, 2 (67) :pe24

[12] Autophagy influences glomerular disease susceptibility and maintains podocyte homeostasis in aging mice [J].

Hartleben, Bjoern ;

Goedel, Markus ;

Meyer-Schwesinger, Catherine ;

Liu, Shuya ;

Ulrich, Theresa ;

Koebler, Sven ;

Wiech, Thorsten ;

Grahammer, Florian ;

Arnold, Sebastian J. ;

Lindenmeyer, Maja T. ;

Cohen, Clemens D. ;

Pavenstaedt, Hermann ;

Kerjaschki, Dontscho ;

Mizushima, Noboru ;

Shaw, Andrey S. ;

Walz, Gerd ;

Huber, Tobias B. .

JOURNAL OF CLINICAL INVESTIGATION, 2010, 120 (04) :1084-1096

[13] mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice [J].

Inoki, Ken ;

Mori, Hiroyuki ;

Wang, Junying ;

Suzuki, Tsukasa ;

Hong, SungKi ;

Yoshida, Sei ;

Blattner, Simone M. ;

Ikenoue, Tsuneo ;

Rueegg, Markus A. ;

Hall, Michael N. ;

Kwiatkowski, David J. ;

Rastaldi, Maria P. ;

Huber, Tobias B. ;

Kretzler, Matthias ;

Holzman, Lawrence B. ;

Wiggins, Roger C. ;

Guan, Kun-Liang .

JOURNAL OF CLINICAL INVESTIGATION, 2011, 121 (06) :2181-2196

[14] Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive [J].

Jacinto, E ;

Loewith, R ;

Schmidt, A ;

Lin, S ;

Rüegg, MA ;

Hall, A ;

Hall, MN .

NATURE CELL BIOLOGY, 2004, 6 (11) :1122-U30

[15] Nck adaptor proteins link nephrin to the actin cytoskeleton of kidney podocytes [J].

Jones, N ;

Blasutig, IM ;

Eremina, V ;

Ruston, JM ;

Bladt, F ;

Li, HP ;

Huang, HM ;

Larose, L ;

Li, SSC ;

Takano, T ;

Quaggin, SE ;

Pawson, T .

NATURE, 2006, 440 (7085) :818-823

[16] Hypoxia-inducible factor 1α is regulated by the mammalian target of rapamycin (mTOR) via an mTOR signaling motif [J].

Land, Stephen C. ;

Tee, Andrew R. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2007, 282 (28) :20534-20543

[17] High sirolimus levels may induce focal segmental glomerulosclerosis de novo [J].

Letavernier, Emmanuel ;

Bruneval, Patrick ;

Mandet, Chantal ;

Van Huyen, Jean-Paul Duong ;

Peraldi, Marie-Noelle ;

Helal, Imed ;

Noel, Laure-Helene ;

Legendre, Christophe .

CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2007, 2 (02) :326-333

[18] A highly efficient recombineering-based method for generating conditional knockout mutations [J].

Liu, PT ;

Jenkins, NA ;

Copeland, NG .

GENOME RESEARCH, 2003, 13 (03) :476-484

[19] Defective CFTR induces aggresome formation and lung inflammation in cystic fibrosis through ROS-mediated autophagy inhibition [J].

Luciani, Alessandro ;

Villella, Valeria Rachela ;

Esposito, Speranza ;

Brunetti-Pierri, Nicola ;

Medina, Diego ;

Settembre, Carmine ;

Gavina, Manuela ;

Pulze, Laura ;

Giardino, Ida ;

Pettoello-Mantovani, Massimo ;

D'Apolito, Maria ;

Guido, Stefano ;

Masliah, Eliezer ;

Spencer, Brian ;

Quaratino, Sonia ;

Raia, Valeria ;

Ballabio, Andrea ;

Maiuri, Luigi .

NATURE CELL BIOLOGY, 2010, 12 (09) :863-875

[20] Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfimction, hypertension, and proteinuria in preeclampsia [J].

Maynard, SE ;

Min, JY ;

Merchan, J ;

Lim, KH ;

Li, JY ;

Mondal, S ;

Libermann, TA ;

Morgan, LP ;

Sellke, FW ;

Stillman, IE ;

Epstein, FH ;

Sukhatme, VP ;

Karumanchi, SA .

JOURNAL OF CLINICAL INVESTIGATION, 2003, 111 (05) :649-658

← 1 2 3 4 →