PMID- 25694483
OWN - NLM
STAT- MEDLINE
DCOM- 20150804
LR  - 20220129
IS  - 1522-1466 (Electronic)
IS  - 1522-1466 (Linking)
VI  - 308
IP  - 10
DP  - 2015 May 15
TI  - The swan-neck lesion: proximal tubular adaptation to oxidative stress in 
      nephropathic cystinosis.
PG  - F1155-66
LID - 10.1152/ajprenal.00591.2014 [doi]
AB  - Cystinosis is an inherited disorder resulting from a mutation in the CTNS gene, 
      causing progressive proximal tubular cell flattening, the so-called swan-neck 
      lesion (SNL), and eventual renal failure. To determine the role of oxidative 
      stress in cystinosis, histologic sections of kidneys from C57BL/6 Ctns(-/-) and 
      wild-type mice were examined by immunohistochemistry and morphometry from 1 wk to 
      20 mo of age. Additional mice were treated from 1 to 6 mo with vehicle or 
      mitoquinone (MitoQ), an antioxidant targeted to mitochondria. The leading edge of 
      the SNL lost mitochondria and superoxide production, and became surrounded by a 
      thickened tubular basement membrane. Progression of the SNL as determined by 
      staining with lectin from Lotus tetragonolobus accelerated after 3 mo, but was 
      delayed by treatment with MitoQ (38 +/- 4% vs. 28 +/- 1%, P < 0.01). Through 9 mo, 
      glomeruli had retained renin staining and intact macula densa, whereas SNL 
      expressed transgelin, an actin-binding protein, but neither kidney injury 
      molecule-1 (KIM-1) nor cell death was observed. After 9 mo, clusters of proximal 
      tubules exhibited localized oxidative stress (4-hydroxynonenal binding), 
      expressed KIM-1, and underwent apoptosis, leading to the formation of atubular 
      glomeruli and accumulation of interstitial collagen. We conclude that nephron 
      integrity is initially maintained in the Ctns(-/-) mouse by adaptive flattening 
      of cells of the SNL through loss of mitochondria, upregulation of transgelin, and 
      thickened basement membrane. This adaptation ultimately fails in adulthood, with 
      proximal tubular disruption, formation of atubular glomeruli, and renal failure. 
      Antioxidant treatment targeted to mitochondria delays initiation of the SNL, and 
      may provide therapeutic benefit in children with cystinosis.
CI  - Copyright (c) 2015 the American Physiological Society.
FAU - Galarreta, Carolina I
AU  - Galarreta CI
AD  - Department of Pediatrics, University of Virginia, Charlottesville, Virginia;
FAU - Forbes, Michael S
AU  - Forbes MS
AD  - Department of Pediatrics, University of Virginia, Charlottesville, Virginia;
FAU - Thornhill, Barbara A
AU  - Thornhill BA
AD  - Department of Pediatrics, University of Virginia, Charlottesville, Virginia;
FAU - Antignac, Corinne
AU  - Antignac C
AD  - Inserm U1163, Laboratory of Hereditary Kidney Diseases, and Paris 
      Descartes-Sorbonne Paris Cite University, Imagine Institute, Paris, France; and.
FAU - Gubler, Marie-Claire
AU  - Gubler MC
AD  - Inserm U1163, Laboratory of Hereditary Kidney Diseases, and Paris 
      Descartes-Sorbonne Paris Cite University, Imagine Institute, Paris, France; and.
FAU - Nevo, Nathalie
AU  - Nevo N
AD  - Inserm U1163, Laboratory of Hereditary Kidney Diseases, and Paris 
      Descartes-Sorbonne Paris Cite University, Imagine Institute, Paris, France; and.
FAU - Murphy, Michael P
AU  - Murphy MP
AD  - MRC Mitochondrial Biology Unit, Cambridge, United Kingdom.
FAU - Chevalier, Robert L
AU  - Chevalier RL
AD  - Department of Pediatrics, University of Virginia, Charlottesville, Virginia; 
      RLC2M@virginia.edu.
LA  - eng
GR  - MC_U105663142/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150218
PL  - United States
TA  - Am J Physiol Renal Physiol
JT  - American journal of physiology. Renal physiology
JID - 100901990
RN  - 0 (Amino Acid Transport Systems, Neutral)
RN  - 0 (Antioxidants)
RN  - 0 (Havcr1 protein, mouse)
RN  - 0 (Hepatitis A Virus Cellular Receptor 1)
RN  - 0 (Membrane Proteins)
RN  - 0 (Organophosphorus Compounds)
RN  - 0 (cystinosin protein, mouse)
RN  - 11062-77-4 (Superoxides)
RN  - 1339-63-5 (Ubiquinone)
RN  - 47BYS17IY0 (mitoquinone)
SB  - IM
MH  - Adaptation, Physiological/*physiology
MH  - Amino Acid Transport Systems, Neutral/deficiency/genetics/metabolism
MH  - Animals
MH  - Antioxidants/pharmacology
MH  - Apoptosis/drug effects
MH  - Cystinosis/genetics/*pathology/*physiopathology
MH  - Disease Models, Animal
MH  - Female
MH  - Hepatitis A Virus Cellular Receptor 1
MH  - Kidney Tubules, Proximal/metabolism/*pathology/*physiopathology
MH  - Male
MH  - Membrane Proteins/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Mitochondria/drug effects
MH  - Mutation/genetics
MH  - Organophosphorus Compounds/pharmacology
MH  - Oxidative Stress/*physiology
MH  - Superoxides/metabolism
MH  - Ubiquinone/analogs & derivatives/pharmacology
OTO - NOTNLM
OT  - cystinosis
OT  - mitoquinone
OT  - oxidative injury
OT  - proximal tubule
OT  - swan-neck lesion
EDAT- 2015/02/20 06:00
MHDA- 2015/08/05 06:00
CRDT- 2015/02/20 06:00
PHST- 2014/10/24 00:00 [received]
PHST- 2015/02/09 00:00 [accepted]
PHST- 2015/02/20 06:00 [entrez]
PHST- 2015/02/20 06:00 [pubmed]
PHST- 2015/08/05 06:00 [medline]
AID - ajprenal.00591.2014 [pii]
AID - 10.1152/ajprenal.00591.2014 [doi]
PST - ppublish
SO  - Am J Physiol Renal Physiol. 2015 May 15;308(10):F1155-66. doi: 
      10.1152/ajprenal.00591.2014. Epub 2015 Feb 18.