title: Megalin and cubilin in proximal tubule protein reabsorption: from experimental models to human disease.
abstract: Proximal tubule protein uptake is mediated by 2 receptors, megalin and cubilin. These receptors rescue a variety of filtered ligands, including biomarkers, essential vitamins, and hormones. Receptor gene knockout animal models have identified important functions of the receptors and have established their essential role in modulating urinary protein excretion. Rare genetic syndromes associated with dysfunction of these receptors have been identified and characterized, providing additional information on the importance of these receptors in humans. Using various disease models in combination with receptor gene knockout, the implications of receptor dysfunction in acute and chronic kidney injury have been explored and have pointed to potential new roles of these receptors. Based on data from animal models, this paper will review current knowledge on proximal tubule endocytic receptor function and regulation, and their role in renal development, protein reabsorption, albumin uptake, and normal renal physiology. These findings have implications for the pathophysiology and diagnosis of proteinuric renal diseases. We will examine the limitations of the different models and compare the findings to phenotypic observations in inherited human disorders associated with receptor dysfunction. Furthermore, evidence from receptor knockout mouse models as well as human observations suggesting a role of protein receptors for renal disease will be discussed in light of conditions such as chronic kidney disease, diabetes, and hypertension.
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Rikke
authors.initials: R
authors.lastname: Nielsen
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Erik Ilsø
authors.initials: EI
authors.lastname: Christensen
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark; Department of Renal Medicine, Aarhus University Hospital, Aarhus, Denmark. Electronic address: hb@ana.au.dk.
authors.forename: Henrik
authors.initials: H
authors.lastname: Birn
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000235:genetics / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology*; D051436:Renal Insufficiency, Chronic / Q000378:metabolism*
chemical_list: D026561:Low Density Lipoprotein Receptor-Related Protein-2; D011956:Receptors, Cell Surface; C029486:intrinsic factor-cobalamin receptor
keywords: Fanconi syndrome; albuminuria; endocytosis; proximal tubule