PMID- 24092929
OWN - NLM
STAT- MEDLINE
DCOM- 20131223
LR  - 20220410
IS  - 1533-3450 (Electronic)
IS  - 1046-6673 (Print)
IS  - 1046-6673 (Linking)
VI  - 24
IP  - 11
DP  - 2013 Nov
TI  - Obesity-mediated autophagy insufficiency exacerbates proteinuria-induced 
      tubulointerstitial lesions.
PG  - 1769-81
LID - 10.1681/ASN.2012111080 [doi]
AB  - Obesity is an independent risk factor for renal dysfunction in patients with 
      CKDs, including diabetic nephropathy, but the mechanism underlying this 
      connection remains unclear. Autophagy is an intracellular degradation system that 
      maintains intracellular homeostasis by removing damaged proteins and organelles, 
      and autophagy insufficiency is associated with the pathogenesis of 
      obesity-related diseases. We therefore examined the role of autophagy in 
      obesity-mediated exacerbation of proteinuria-induced proximal tubular epithelial 
      cell damage in mice and in human renal biopsy specimens. In nonobese mice, overt 
      proteinuria, induced by intraperitoneal free fatty acid-albumin overload, led to 
      mild tubular damage and apoptosis, and activated autophagy in proximal tubules 
      reabsorbing urinary albumin. In contrast, diet-induced obesity suppressed 
      proteinuria-induced autophagy and exacerbated proteinuria-induced tubular cell 
      damage. Proximal tubule-specific autophagy-deficient mice, resulting from an Atg5 
      gene deletion, subjected to intraperitoneal free fatty acid-albumin overload 
      developed severe proteinuria-induced tubular damage, suggesting that 
      proteinuria-induced autophagy is renoprotective. Mammalian target of rapamycin 
      (mTOR), a potent suppressor of autophagy, was activated in proximal tubules of 
      obese mice, and treatment with an mTOR inhibitor ameliorated obesity-mediated 
      autophagy insufficiency. Furthermore, both mTOR hyperactivation and autophagy 
      suppression were observed in tubular cells of specimens obtained from obese 
      patients with proteinuria. Thus, in addition to enhancing the understanding of 
      obesity-related cell vulnerability in the kidneys, these results suggest that 
      restoring the renoprotective action of autophagy in proximal tubules may improve 
      renal outcomes in obese patients.
FAU - Yamahara, Kosuke
AU  - Yamahara K
AD  - Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan;
FAU - Kume, Shinji
AU  - Kume S
FAU - Koya, Daisuke
AU  - Koya D
FAU - Tanaka, Yuki
AU  - Tanaka Y
FAU - Morita, Yoshikata
AU  - Morita Y
FAU - Chin-Kanasaki, Masami
AU  - Chin-Kanasaki M
FAU - Araki, Hisazumi
AU  - Araki H
FAU - Isshiki, Keiji
AU  - Isshiki K
FAU - Araki, Shin-ichi
AU  - Araki S
FAU - Haneda, Masakazu
AU  - Haneda M
FAU - Matsusaka, Taiji
AU  - Matsusaka T
FAU - Kashiwagi, Atsunori
AU  - Kashiwagi A
FAU - Maegawa, Hiroshi
AU  - Maegawa H
FAU - Uzu, Takashi
AU  - Uzu T
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20131003
PL  - United States
TA  - J Am Soc Nephrol
JT  - Journal of the American Society of Nephrology : JASN
JID - 9013836
RN  - 0 (Gtf2h1 protein, mouse)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Transcription Factors)
RN  - 148710-81-0 (Transcription Factor TFIIH)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
CIN - J Am Soc Nephrol. 2013 Nov;24(11):1711-3. PMID: 24092931
MH  - Animals
MH  - Autophagy/*physiology
MH  - Cells, Cultured
MH  - Diet, High-Fat
MH  - Endoplasmic Reticulum Stress
MH  - Epithelial Cells/pathology
MH  - Kidney Tubules, Proximal/*pathology
MH  - Male
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Multiprotein Complexes/physiology
MH  - Obesity/*complications
MH  - Proteinuria/*complications
MH  - TOR Serine-Threonine Kinases/physiology
MH  - Transcription Factor TFIIH
MH  - Transcription Factors/metabolism
PMC - PMC3810079
EDAT- 2013/10/05 06:00
MHDA- 2013/12/24 06:00
PMCR- 2014/11/01
CRDT- 2013/10/05 06:00
PHST- 2013/10/05 06:00 [entrez]
PHST- 2013/10/05 06:00 [pubmed]
PHST- 2013/12/24 06:00 [medline]
PHST- 2014/11/01 00:00 [pmc-release]
AID - ASN.2012111080 [pii]
AID - 2012111080 [pii]
AID - 10.1681/ASN.2012111080 [doi]
PST - ppublish
SO  - J Am Soc Nephrol. 2013 Nov;24(11):1769-81. doi: 10.1681/ASN.2012111080. Epub 2013 
      Oct 3.