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.

Site-specific O-glycosylation of members of the low-density lipoprotein receptor superfamily enhances ligand interactions

“…We extended these studies to include comprehensive analysis of LDLR-related proteins in rat liver, brain and kidney (Fig. 1, labeled 4 and Suppl. Dataset 2), and we were able to confirm four out of the four predicted glycosites in the XX-C6XXXTC1-XX linker regions of LDLR, three out of five in VLDLR, seven out of eight in LRP1, and eight out of 10 in LRP2 (rat LRP2 has three fewer predicted glycosites than human between LA1-2, 23-24, and 30-31).…”

“…The LDLR superfamily includes the VLDL receptor (VLDLR), LDLR-related protein 1 (LRP1), LDLR-related protein 1B (LRP1B), LDLR-related protein 2 (LRP2 or megalin) and LDLR-related protein 8 (LRP8 or ApoER2), as well as more distantly related receptors such as the Sortilin-related receptor (SORLA) (1). These members also have important roles in cardiovascular diseases as well as neurodegenerative and proteinuric renal diseases (3)(4). The ectodomains of LDLR-related proteins share characteristic structural features including LDLR-type A repeats (LA) (complement-like cysteine-rich ligand binding repeats), EGF-like repeats, and YWTD beta-propeller domains (1).…”

Kidney Cadmium Toxicity, Diabetes and High Blood Pressure: The Perfect Storm

“…Thus, it is suggested that Cd reabsorption is mediated by receptor-mediated endocytosis, involving the multi-ligand receptors, megalin and cubulin Thevenod and Wolff 2016). These two multi-ligand receptors are localized to the apical membrane of PT cells, and they are responsible for reabsorption of the all proteins, notably albumin and MT, present in the glomerular filtrate (Nielsen et al 2016).…”

Megalin Is Predominantly Observed in Vesicular Structures in First and Third Trimester Cytotrophoblasts of the Human Placenta

“…Megalin has predominantly been studied in the kidney proximal tubular epithelium. [14][15][16] Here, it localizes to the apical membrane as well as the endolysosomal apparatus of proximal tubular cells and mediates reabsorption of many different ligands from the glomerular ultrafiltrate. [14][15][16] Megalin has furthermore been shown to be expressed in both cytotrophoblasts and syncytiotrophoblasts of human placenta and, here, suggested to function as a nutrient receptor and mediate uptake of nutrients from the maternal bloodstream (similar to its functions in the kidney).…”

“…[14][15][16] Here, it localizes to the apical membrane as well as the endolysosomal apparatus of proximal tubular cells and mediates reabsorption of many different ligands from the glomerular ultrafiltrate. [14][15][16] Megalin has furthermore been shown to be expressed in both cytotrophoblasts and syncytiotrophoblasts of human placenta and, here, suggested to function as a nutrient receptor and mediate uptake of nutrients from the maternal bloodstream (similar to its functions in the kidney). [17][18][19][20][21] However, the function of placental megalin has not been systematically investigated in suitable models, and the suggestions regarding the role of megalin in human placenta therefore remain purely speculative.…”