title: Role of mTOR in podocyte function and diabetic nephropathy in humans and mice.
abstract: Chronic glomerular diseases, associated with renal failure and cardiovascular morbidity, represent a major health issue. However, they remain poorly understood. Here we have reported that tightly controlled mTOR activity was crucial to maintaining glomerular podocyte function, while dysregulation of mTOR facilitated glomerular diseases. Genetic deletion of mTOR complex 1 (mTORC1) in mouse podocytes induced proteinuria and progressive glomerulosclerosis. Furthermore, simultaneous deletion of both mTORC1 and mTORC2 from mouse podocytes aggravated the glomerular lesions, revealing the importance of both mTOR complexes for podocyte homeostasis. In contrast, increased mTOR activity accompanied human diabetic nephropathy, characterized by early glomerular hypertrophy and hyperfiltration. Curtailing mTORC1 signaling in mice by genetically reducing mTORC1 copy number in podocytes prevented glomerulosclerosis and significantly ameliorated the progression of glomerular disease in diabetic nephropathy. These results demonstrate the requirement for tightly balanced mTOR activity in podocyte homeostasis and suggest that mTOR inhibition can protect podocytes and prevent progressive diabetic nephropathy.
authors: Renal Division, University Hospital Freiburg, Freiburg, Germany.
authors: Markus
authors: M
authors: Gödel
authors: Björn
authors: B
authors: Hartleben
authors: Nadja
authors: N
authors: Herbach
authors: Shuya
authors: S
authors: Liu
authors: Stefan
authors: S
authors: Zschiedrich
authors: Shun
authors: S
authors: Lu
authors: Andrea
authors: A
authors: Debreczeni-Mór
authors: Maja T
authors: MT
authors: Lindenmeyer
authors: Maria-Pia
authors: MP
authors: Rastaldi
authors: Götz
authors: G
authors: Hartleben
authors: Thorsten
authors: T
authors: Wiech
authors: Alessia
authors: A
authors: Fornoni
authors: Robert G
authors: RG
authors: Nelson
authors: Matthias
authors: M
authors: Kretzler
authors: Rüdiger
authors: R
authors: Wanke
authors: Hermann
authors: H
authors: Pavenstädt
authors: Dontscho
authors: D
authors: Kerjaschki
authors: Clemens D
authors: CD
authors: Cohen
authors: Michael N
authors: MN
authors: Hall
authors: Markus A
authors: MA
authors: Rüegg
authors: Ken
authors: K
authors: Inoki
authors: Gerd
authors: G
authors: Walz
authors: Tobias B
authors: TB
authors: Huber
references: J Am Soc Nephrol. 2005 Oct;16(10):2953-66
references: 16120818
references: J Microsc. 1984 May;134(Pt 2):127-36
references: 6737468
references: Cell Metab. 2008 Nov;8(5):399-410
references: 19046571
references: Nephrol Dial Transplant. 2007 Aug;22(8):2175-82
references: 17550925
references: J Am Soc Nephrol. 2009 Jul;20(7):1533-43
references: 19443634
references: Kidney Int. 1991 Jul;40(1):29-34
references: 1921152
references: Mol Cell. 2006 Apr 21;22(2):159-68
references: 16603397
references: J Am Soc Nephrol. 2006 May;17(5):1395-404
references: 16597691
references: PLoS One. 2008 Aug 13;3(8):e2937
references: 18698414
references: Genes Dev. 2008 Sep 15;22(18):2485-95
references: 18794346
references: Biochem Biophys Res Commun. 2006 Feb 3;340(1):296-301
references: 16364254
references: Diabetes Res Clin Pract. 2008 Nov 13;82 Suppl 1:S59-62
references: 18926585
references: Curr Opin Cell Biol. 2009 Apr;21(2):209-18
references: 19261457
references: Am J Pathol. 1987 Oct;129(1):64-73
references: 3661680
references: Adv Intern Med. 2001;46:359-408
references: 11147259
references: Am J Pathol. 2002 Sep;161(3):799-805
references: 12213707
references: Proc Natl Acad Sci U S A. 2006 Apr 11;103(15):5682-7
references: 16581909
references: N Engl J Med. 2005 Nov 10;353(19):2088-9
references: 16282189
references: Diabetologia. 1975 Jun;11(3):225-9
references: 1149955
references: J Am Soc Nephrol. 2005 Oct;16(10):3102-9
references: 16107583
references: Diabetes. 2009 Feb;58(2):469-77
references: 19017763
references: J Clin Invest. 2011 Jun;121(6):2181-96
references: 21606597
references: Kidney Int. 1999 Apr;55(4):1462-9
references: 10201011
references: N Engl J Med. 2008 Mar 13;358(11):1129-36
references: 18337603
references: Am J Physiol Renal Physiol. 2009 Apr;296(4):F819-29
references: 19211686
references: Cell Metab. 2010 Oct 6;12(4):329-340
references: 20889126
references: J Cell Biol. 2004 Jul 19;166(2):213-23
references: 15249583
references: J Clin Invest. 2010 Apr;120(4):1084-96
references: 20200449
references: Clin J Am Soc Nephrol. 2007 Mar;2(2):326-33
references: 17699432
references: EMBO J. 2006 Jun 21;25(12):2781-91
references: 16763566
references: Kidney Int. 2002 Jan;61(1):133-40
references: 11786093
references: FASEB J. 2002 Nov;16(13):1721-31
references: 12409314
references: Genesis. 2007 Sep;45(9):593-605
references: 17868096
references: Biochem Biophys Res Commun. 2009 Jul 10;384(4):471-5
references: 19422788
references: Genesis. 2003 Jan;35(1):39-42
references: 12481297
references: J Anat. 1980 May;130(Pt 3):595-602
references: 7410201
references: J Am Soc Nephrol. 2009 Dec;20(12):2490-2
references: 19820126
references: Nephrol Dial Transplant. 2009 Dec;24(12):3632-40
references: 19671594
references: Science. 1999 Sep 24;285(5436):2126-9
references: 10497130
references: Mol Cell Biol. 2004 Aug;24(15):6710-8
references: 15254238
references: Diabetes. 2007 Feb;56(2):346-54
references: 17259378
references: Curr Opin Nephrol Hypertens. 2011 Jan;20(1):56-61
references: 21088575
references: J Am Soc Nephrol. 2005 Jun;16(6):1703-10
references: 15872080
references: J Cell Sci. 2009 Oct 15;122(Pt 20):3589-94
references: 19812304
references: J Appl Physiol. 1962 Mar;17:343-8
references: 14005589
references: Lab Invest. 1993 Jan;68(1):56-61
references: 8423677
references: Mol Cell Biol. 2004 Nov;24(21):9508-16
references: 15485918
references: J Am Soc Nephrol. 2009 Dec;20(12):2493-502
references: 19875810
references: J Clin Invest. 2010 Nov;120(11):4040-54
references: 20978353
references: Histol Histopathol. 2010 Feb;25(2):189-96
references: 20017105
references: Cell. 2005 Nov 18;123(4):569-80
references: 16286006
references: Nature. 2004 Sep 9;431(7005):200-5
references: 15306821
references: Science. 2005 Feb 18;307(5712):1098-101
references: 15718470
references: Nat Med. 2008 Mar;14(3):290-8
references: 18311147
references: J Am Soc Nephrol. 2005 Oct;16(10):2830-2
references: 16148037
references: Genes Dev. 2000 Nov 1;14(21):2712-24
references: 11069888
references: Cell. 2006 Feb 10;124(3):471-84
references: 16469695
references: Cell Metab. 2008 Nov;8(5):411-24
references: 19046572