Beyond the tubule: pathological variants of LRP2, encoding the megalin receptor, result in glomerular loss and early progressive chronic kidney disease

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Beyond the tubule : pathological variants of LRP2, encoding the megalin receptor, result in glomerular loss and early progressive chronic kidney disease

Charlton, Jennifer R. (author): Univ Virginia, Dept Pediat, Div Nephrol, Charlottesville, VA USA.

Tan, Weizhen (author): Massachusetts Gen Hosp Children, Div Nephrol, Boston, MA USA.

Daouk, Ghaleb (author): Massachusetts Gen Hosp Children, Div Nephrol, Boston, MA USA.

Teot, Lisa (author): Boston Childrens Hosp, Dept Pathol, Boston, MA USA.

Rosen, Seymour (author): Boston Childrens Hosp, Dept Pathol, Boston, MA USA.;Beth Israel Deaconess Med Ctr, Dept Pathol, 330 Brookline Ave, Boston, MA 02215 USA.

Bennett, Kevin M. (author): Washington Univ, Dept Radiol, St Louis, MO 63110 USA.

Cwiek, Aleksandra (author): Univ Virginia, Dept Pediat, Div Nephrol, Charlottesville, VA USA.

Nam, Sejin (author): Univ Hawaii Manoa, Dept Phys, Manoa, HI USA.

Emma, Francesco (author): Bambino Gesu Pediat Hosp, Ist Ricovero & Cura Carattere Sci, Dept Pediat Subspecialties, Div Nephrol, Rome, Italy.

Jouret, Francois (author): Univ Liege, Unit Cardiovasc Sci, Grp Interdisciplinaire Genoprote Appl, Liege, Belgium.

Oliveira, Joao Paulo (author): Sao Joao Univ Hosp Ctr, Serv Med Genet, Porto, Portugal.;Univ Porto, Fac Med, Porto, Portugal.;I3S Inst Hlth Res & Innovat, Porto, Portugal.

Tranebjaerg, Lisbeth (author): Rigshosp, Kennedy Ctr, Dept Clin Genet, Copenhagen, Denmark.;Univ Copenhagen, Inst Clin Med, Panum Inst, Copenhagen, Denmark.

Frykholm, Carina (author): Uppsala universitet,Medicinsk genetik och genomik

Mane, Shrikant (author): Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA.

Hildebrandt, Friedhelm (author): Harvard Med Sch, Boston Childrens Hosp, Dept Med, Boston, MA 02115 USA.

Srivastava, Tarak (author): Childrens Mercy Hosp, Kansas City, MO 64108 USA.

Storm, Tina (author): Aarhus Univ, Dept Biomed, Aarhus, Denmark.

Christensen, Erik Ilsö (author): Aarhus Univ, Dept Biomed, Aarhus, Denmark.

Nielsen, Rikke (author): Aarhus Univ, Dept Biomed, Aarhus, Denmark.

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Univ Virginia, Dept Pediat, Div Nephrol, Charlottesville, VA USA Massachusetts Gen Hosp Children, Div Nephrol, Boston, MA USA. (creator_code:org_t)

AMER PHYSIOLOGICAL SOC, 2020
2020
English.
In: American Journal of Physiology - Renal Physiology. - : AMER PHYSIOLOGICAL SOC. - 1931-857X .- 1522-1466. ; 319:6, s. F988-F999

Related links:: https://www.ncbi.nlm...; show more...; https://urn.kb.se/re...; https://doi.org/10.1...; show less...

Journal article (peer-reviewed)

Abstract Subject headings

Pathogenic variants in the LRP2 gene, encoding the multiligand receptor megalin, cause a rare autosomal recessive syndrome: Donnai-Barrow/Facio-Oculo-Acoustico-Renal (DB/FOAR) syndrome. Because of the rarity of the syndrome, the long-term consequences of the tubulopathy on human renal health have been difficult to ascertain, and the human clinical condition has hitherto been characterized as a benign tubular condition with asymptomatic low-molecularweight proteinuria. We investigated renal function and morphology in a murine model of DB/FOAR syndrome and in patients with DB/FOAR. We analyzed glomerular filtration rate in mice by FETC-inulin clearance and clinically characterized six families, including nine patients with DB/FOAR and nine family members. Urine samples from patients were analyzed by Western blot analysis and biopsy materials were analyzed by histology. In the mouse model, we used histological methods to assess nephrogenesis and postnatal renal structure and contrast-enhanced magnetic resonance imaging to assess glomerular number. In megalin-deficient mice, we found a lower glomerular filtration rate and an increase in the abundance of injury markers, such as kidney injury molecule-1 and N-acetyl-11-n-glucosaminidase. Renal injury was validated in patients, who presented with increased urinary kidney injury molecule-1, classical markers of chronic kidney disease, and glomerular proteinuria early in life. Megalin-deficient mice had normal nephrogenesis, but they had 19% fewer nephrons in early adulthood and an increased fraction of nephrons with disconnected glomerulotubular junction. In conclusion, megalin dysfunction, as present in DB/FOAR syndrome, confers an increased risk of progression into chronic kidney disease.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Urologi och njurmedicin (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Urology and Nephrology (hsv//eng)

Keyword

cationic ferritin-enhanced magnetic resonance imaging
glomerular number
kidney disease etiology
megalin
nephron loss
proximal tubule

Publication and Content Type

ref (subject category)
art (subject category)

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