ABSTRACT
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.
Subject(s)
Agenesis of Corpus Callosum/diagnosis , Hearing Loss, Sensorineural/diagnosis , Hernias, Diaphragmatic, Congenital/diagnosis , Kidney Tubules, Proximal/physiopathology , Myopia/diagnosis , Proteinuria/diagnosis , Renal Tubular Transport, Inborn Errors/diagnosis , Agenesis of Corpus Callosum/genetics , Agenesis of Corpus Callosum/physiopathology , Agenesis of Corpus Callosum/urine , Biopsy , Carbonic Anhydrase III/urine , Child, Preschool , DNA Mutational Analysis , Endocytosis , Female , Genetic Predisposition to Disease , Hearing Loss, Sensorineural/genetics , Hearing Loss, Sensorineural/physiopathology , Hearing Loss, Sensorineural/urine , Hernias, Diaphragmatic, Congenital/genetics , Hernias, Diaphragmatic, Congenital/physiopathology , Hernias, Diaphragmatic, Congenital/urine , Humans , Immunohistochemistry , Kidney Tubules, Proximal/metabolism , Kidney Tubules, Proximal/ultrastructure , Low Density Lipoprotein Receptor-Related Protein-2/genetics , Microscopy, Electron , Mutation , Myopia/genetics , Myopia/physiopathology , Myopia/urine , Phenotype , Predictive Value of Tests , Prognosis , Proteinuria/genetics , Proteinuria/physiopathology , Proteinuria/urine , Receptors, Cell Surface/metabolism , Renal Tubular Transport, Inborn Errors/genetics , Renal Tubular Transport, Inborn Errors/physiopathology , Renal Tubular Transport, Inborn Errors/urineABSTRACT
Dysfunction of the proximal tubule (PT) is associated with variable degrees of solute wasting and low-molecular-weight proteinuria. We measured metabolic consequences and adaptation mechanisms in a model of inherited PT disorders using PT cells of ClC-5-deficient (Clcn5Y/-) mice, a well-established model of Dent's disease. Compared to cells taken from control mice, those from the mutant mice had increased expression of markers of proliferation (Ki67, proliferative cell nuclear antigen (PCNA), and cyclin E) and oxidative scavengers (superoxide dismutase I and thioredoxin). Transcriptome and protein analyses showed fourfold induction of type III carbonic anhydrase in a kidney-specific manner in the knockout mice located in scattered PT cells. Kidney-specific carbonic anhydrase type III (CAIII) upregulation was confirmed in other mice lacking the multiligand receptor megalin and in a patient with Dent's disease due to an inactivating CLCN5 mutation. The type III enzyme was specifically detected in the urine of mice lacking ClC-5 or megalin, patients with Dent's disease, and in PT cell lines exposed to oxidative stress. Our study shows that lack of PT ClC-5 in mice and men is associated with CAIII induction, increased cell proliferation, and oxidative stress.