Renal phenotypic investigations of megalin-deficient patients: novel insights into tubular proteinuria and albumin filtration*

Storm, Tina; Tranebjærg, Lisbeth; Frykholm, Carina; Birn, Henrik; Verroust, P; Nevéus, Tryggve; Sundelin, Birgitta; Hertz, Jens Michael; Holmström, Gerd; Ericson, Katharina; Christensen, Erik; Nielsen, Rikke

doi:10.1093/ndt/gfs462

Cited by 75 publications

(83 citation statements)

References 20 publications

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“…b Similar urinary samples were separated by SDS-PAGE, transferred onto a nitrocellulose membrane and blotted with antibodies against cubilin (from Ref. [3]), type 3 carbonic anhydrase (CAIII, from Ref. [8]) or Tamm-Horsfall protein (UMOD, from Ref.…”

Section: Discussionmentioning

confidence: 99%

“…Serial sections (as notified by the asterisk located in the same renal tubule) were incubated with primary antibodies against megalin (from Ref. [3]), aquaporin-1 (from Ref. [15]), cubilin (from Ref.…”

Section: Discussionmentioning

confidence: 99%

“…[15]), cubilin (from Ref. [3]) or type III carbonic anhydrase (CAIII, from Ref. [8]), followed by incubation with ad hoc horseradish-conjugated secondary antibodies.…”

Section: Discussionmentioning

confidence: 99%

“…CAIII may participate in PT cell response to oxidative damage proteinuria [2]. The amount of physiological glomerular filtration of albumin remains debated [3]. In mice, PT uptake of filtered albumin relies on the co-expression of megalin and cubilin [1].…”

Section: Discussionmentioning

confidence: 99%

“…Megalin is a multi-ligand receptor encoded by the LRP2 gene, and belongs to the low-density lipoprotein (LDL) receptor family [2]. Mutations of LRP2 cause autosomal recessive Donnai-Barrow/facio-oculo-acoustico-renal syndrome (DB/ FOAR), whose cardinal features include: corpus callosum agenesis, developmental delay, enlarged anterior fontanel, myopia, hypertelorism, sensorineural hearing loss, and LMW proteinuria [2,3]. Megalin-null mice also demonstrate LMW proteinuria, which emphasizes the role of megalin in PT RME [4].…”

Section: Introductionmentioning

confidence: 99%

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In-depth phenotyping of a Donnai–Barrow patient helps clarify proximal tubule dysfunction

et al. 2015

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Background The megalin/cubilin/amnionless complex is essential for albumin and low molecular weight (LMW) protein reabsorption by renal proximal tubules (PT). Mutations of the LRP2 gene encoding megalin cause autosomal recessive Donnai-Barrow/facio-oculo-acoustico-renal syndrome (DB/ FOAR), which is characterized by LMW proteinuria. The pathophysiology of DB/FOAR-associated PT dysfunction remains unclear. Clinical case A 3-year-old girl presented with growth retardation and proteinuria. Clinical examination was unremarkable, except for a still-opened anterior fontanel and myopia. Psychomotor development was delayed. At 6, she developed sensorineural hearing loss. Hypertelorism was noted when she turned 12. Blood analyses, including renal function parameters, were normal. Urine sediment was bland. Proteinuria was significant and included albumin and LMW proteins. Immunoblotting analyses detected cubilin and type 3 carbonic anhydrase (CA3) in the urine. Renal ultrasound was unremarkable. Optical examination of a renal biopsy did not disclose any tubular or glomerular abnormality. Electron microscopy revealed that PT apical endocytic apparatus was significantly less developed. Immunostaining for megalin showed a faint signal in PT cytosol contrasting with the distribution of cubilin at the apical membrane. The diagnostic procedure led to identifying two mutations of the LRP2 gene. Conclusions The functional loss of megalin in DB/FOAR causes PT dysfunction characterized by increased urinary shedding of CA3 and cubilin.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…[15]), cubilin (from Ref. [3]) or type III carbonic anhydrase (CAIII, from Ref. [8]), followed by incubation with ad hoc horseradish-conjugated secondary antibodies.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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In-depth phenotyping of a Donnai–Barrow patient helps clarify proximal tubule dysfunction

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LRP2, an auxiliary receptor that controls sonic hedgehog signaling in development and disease

Christ

Herzog

Willnow

2016

Developmental Dynamics

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To fulfill their multiple roles in organ development and adult tissue homeostasis, hedgehog (HH) morphogens act through their receptor Patched (PTCH) on target cells. However, HH actions also require HH binding proteins, auxiliary cell surface receptors that agonize or antagonize morphogen signaling in a context-dependent manner. Here, we discuss recent findings on the LDL receptor-related protein 2 (LRP2), an exemplary HH binding protein that modulates sonic hedgehog activities in stem and progenitor cell niches in embryonic and adult tissues. LRP2 functions are crucial for developmental processes in a number of tissues, including the brain, the eye, and the heart, and defects in this receptor pathway are the cause of devastating congenital diseases in humans. Developmental Dynamics 245:569-579,

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Sub‐chronic exposure to fluoride impacts the response to a subsequent nephrotoxic treatment with gentamicin

Cárdenas-González

Jacobo-Estrada

Rodríguez-Muñóz

et al. 2015

J of Applied Toxicology

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Fluoride is an important groundwater contaminant, and more than 200 million people are exposed to high fluoride levels in drinking water, the major source of fluoride exposure. Exposure above 2 ppm of fluoride is associated with renal impairment in humans. In rats, moderate levels of fluoride induce kidney injury at early stages in which the glomerular filtration rate (GFR) is not altered. In the present study, we investigated if sub-nephrotoxic stimulus induced by fluoride might impact the response to a subsequent nephrotoxic treatment with gentamicin. Male Wistar rats (~21 days) were exposed to 0, 15 or 50 ppm of fluoride through drinking water during 40 days. Afer that, rats were co-exposed to gentamicin (40 mg kg(-1) day(-1), 7 days). Gentamicin induced a marked decrease in the GFR and an increase in urinary levels as well as the protein and mRNA expression of biomarkers of early kidney injury, such as Kim-1. Interestingly, gentamicin nephrotoxicity was less pronounced in groups previously exposed to fluoride than in the group only treated with gentamicin. Fluoride induced Hsp72, a cytoprotective molecule, which might have improved the response against gentamicin. Moreover, fluoride decreased the expression of megalin, a molecule necessary for internalization of gentamicin into the proximal tubule, potentially reducing gentamicin accumulation. The present results suggest that fluoride reduced gentamicin-induced nephrotoxicity by inducing a compensatory response carried out by Hsp72 and by decreasing gentamicin accumulation. These findings should not be interpreted to suggest that fluoride is a protective agent as megalin deficiency could lead to serious adverse effects on the kidney physiology.

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Renal phenotypic investigations of megalin-deficient patients: novel insights into tubular proteinuria and albumin filtration*

Cited by 75 publications

References 20 publications

In-depth phenotyping of a Donnai–Barrow patient helps clarify proximal tubule dysfunction

In-depth phenotyping of a Donnai–Barrow patient helps clarify proximal tubule dysfunction

LRP2, an auxiliary receptor that controls sonic hedgehog signaling in development and disease

Sub‐chronic exposure to fluoride impacts the response to a subsequent nephrotoxic treatment with gentamicin

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