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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

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

DOI

  • Jennifer R. Charlton, University of Virginia
  • ,
  • Weizhen Tan, Harvard University
  • ,
  • Ghaleb Daouk, Harvard University
  • ,
  • Lisa Teot, Harvard University
  • ,
  • Seymour Rosen, Harvard University
  • ,
  • Kevin M. Bennett, Washington University St. Louis
  • ,
  • Aleksandra Cwiek, University of Virginia
  • ,
  • Sejin Nam, University of Hawaii at Manoa
  • ,
  • Francesco Emma, IRCCS Ospedale pediatrico Bambino Gesù - Roma
  • ,
  • François Jouret, University of Liege
  • ,
  • João Paulo Oliveira, University of Porto
  • ,
  • Lisbeth Tranebjærg, Københavns Universitet
  • ,
  • Carina Frykholm, Uppsala University
  • ,
  • Shrikant Mane, Yale University
  • ,
  • Friedhelm Hildebrandt, Harvard University
  • ,
  • Tarak Srivastava, Children's Mercy Hospitals and Clinics
  • ,
  • Tina Storm
  • ,
  • Erik Ilsø Christensen
  • Rikke Nielsen

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-molecular-weight 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 FITC-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-β-d-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.

OriginalsprogEngelsk
TidsskriftAmerican journal of physiology. Renal physiology
Vol/bind319
Nummer6
Sider (fra-til)F988-F999
ISSN1931-857X
DOI
StatusUdgivet - dec. 2020

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