title: The swan-neck lesion: proximal tubular adaptation to oxidative stress in nephropathic cystinosis.
abstract: 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.
authors.affiliation: Department of Pediatrics, University of Virginia, Charlottesville, Virginia;
authors.forename: Carolina I
authors.initials: CI
authors.lastname: Galarreta
authors.affiliation: Department of Pediatrics, University of Virginia, Charlottesville, Virginia;
authors.forename: Michael S
authors.initials: MS
authors.lastname: Forbes
authors.affiliation: Department of Pediatrics, University of Virginia, Charlottesville, Virginia;
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Thornhill
authors.affiliation: Inserm U1163, Laboratory of Hereditary Kidney Diseases, and Paris Descartes-Sorbonne Paris Cite University, Imagine Institute, Paris, France; and.
authors.forename: Corinne
authors.initials: C
authors.lastname: Antignac
authors.affiliation: Inserm U1163, Laboratory of Hereditary Kidney Diseases, and Paris Descartes-Sorbonne Paris Cite University, Imagine Institute, Paris, France; and.
authors.forename: Marie-Claire
authors.initials: MC
authors.lastname: Gubler
authors.affiliation: Inserm U1163, Laboratory of Hereditary Kidney Diseases, and Paris Descartes-Sorbonne Paris Cite University, Imagine Institute, Paris, France; and.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Nevo
authors.affiliation: MRC Mitochondrial Biology Unit, Cambridge, United Kingdom.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
authors.affiliation: Department of Pediatrics, University of Virginia, Charlottesville, Virginia; RLC2M@virginia.edu.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Chevalier
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology*; D026921:Amino Acid Transport Systems, Neutral / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D003554:Cystinosis / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D000072596:Hepatitis A Virus Cellular Receptor 1; D007687:Kidney Tubules, Proximal / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects; D009154:Mutation / Q000235:genetics; D009943:Organophosphorus Compounds / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology*; D013481:Superoxides / Q000378:metabolism; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D026921:Amino Acid Transport Systems, Neutral; D000975:Antioxidants; C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; D008565:Membrane Proteins; D009943:Organophosphorus Compounds; C534463:cystinosin protein, mouse; D013481:Superoxides; D014451:Ubiquinone; C429014:mitoquinone
keywords: cystinosis; mitoquinone; oxidative injury; proximal tubule; swan-neck lesion