ArticleAmerican journal of physiology. Renal physiology2020
Distinct functions of megalin and cubilin receptors in recovery of normal and nephrotic levels of filtered albumin.
Article in American journal of physiology. Renal physiology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 48 citations in OpenAlex.
- Linagliptin increases the expression of LRP2 independent of Nrf2 in streptozotocin-induced diabetic mice.Journal of diabetes investigation · 2026Article
- Integrative structural analysis of the human LRP2-LRPAP1 complex reveals multiple regulatory sites.Communications biology · 2026Article
- Treatment of glomerular and tubular proteinuria in the nephrotic range in a female cat: case report.Brazilian journal of veterinary medicine · 2026Article
- RNA-based therapeutic opportunities for the treatment of kidney diseases.Nature reviews. Nephrology · 2026Review
- AntimiR uptake by human proximal tubule epithelial cells is predominantly by macropinocytosis.Scientific reports · 2025Article
- Emerging roles of PCSK9 in kidney disease: lipid metabolism, megalin regulation and proteinuria.Pflugers Archiv : European journal of physiology · 2025Review
- TRPML-1 Dysfunction and Renal Tubulopathy in Mucolipidosis Type IV.Journal of the American Society of Nephrology : JASN · 2025Article
- The landscape of renal protein S-acylation in mice with lipid-induced nephrotoxicity.Scientific reports · 2025Article
- Comparison of the Impact of VRP-034 and Polymyxin B upon Markers of Kidney Injury in Human Proximal Tubule Monolayers In Vitro.Antibiotics (Basel, Switzerland) · 2024Article
- Fluid shear stress-induced changes in megalin trafficking enhance endocytic capacity in proximal tubule cells.Frontiers in physiology · 2024Article
- The pathogenesis of albuminuria in cadmium nephropathy.Current research in toxicology · 2024Article
- Evaluation of the efficacy of cystinosin supplementation through CTNS mRNA delivery in experimental models for cystinosis.Scientific reports · 2023Article
- Receptor-associated protein impairs ligand binding to megalin and megalin-dependent endocytic flux in proximal tubule cells.American journal of physiology. Renal physiology · 2023Article
- Megalin, cubilin, and Dab2 drive endocytic flux in kidney proximal tubule cells.Molecular biology of the cell · 2023Article
- Angiotensin II type 2 receptor activation preserves megalin in the kidney and prevents proteinuria in high salt diet fed rats.Scientific reports · 2023Article
- Extended longevity geometrically-inverted proximal tubule organoids.Biomaterials · 2022Article
- Albumin uptake and processing by the proximal tubule: physiological, pathological, and therapeutic implications.Physiological reviews · 2022Review
- Reducing lipid bilayer stress by monounsaturated fatty acids protects renal proximal tubules in diabetes.eLife · 2022Article
- Modelling normal and nephrotic axial uptake of albumin and other filtered proteins along the proximal tubule.The Journal of physiology · 2022Article
- Interference with megalin expression/endocytic function by montelukast mitigates gentamicin nephrotoxicity: Downregulation of ClC-5 expression.Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society · 2022Article
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Authors and funding
10 authors at 2 institutions in 3 countries.
Funding
Abstract
Proximal tubule (PT) cells express a single saturable albumin-binding site whose affinity matches the estimated tubular concentration of albumin; however, albumin uptake capacity is greatly increased under nephrotic conditions. Deciphering the individual contributions of megalin and cubilin to the uptake of normal and nephrotic levels of albumin is impossible in vivo, as knockout of megalin in mice globally disrupts PT endocytic uptake. We quantified concentration-dependent albumin uptake in an optimized opossum kidney cell culture model and fit the kinetic profiles to identify albumin-binding affinities and uptake capacities. Mathematical deconvolution fit best to a three-component model that included saturable high- and low-affinity uptake sites for albumin and underlying nonsaturable uptake consistent with passive uptake of albumin in the fluid phase. Knockdown of cubilin or its chaperone amnionless selectively reduced the binding capacity of the high-affinity site, whereas knockdown of megalin impacted the low-affinity site. Knockdown of disabled-2 decreased the capacities of both binding sites. Additionally, knockdown of megalin or disabled-2 profoundly inhibited the uptake of a fluid phase marker, with cubilin knockdown having a more modest effect. We propose a novel model for albumin retrieval along the PT in which cubilin and megalin receptors have different functions in recovering filtered albumin in proximal tubule cells. Cubilin binding to albumin is tuned to capture normally filtered levels of the protein. In contrast, megalin binding to albumin is of lower affinity, and its expression is also essential for enabling the recovery of high concentrations of albumin in the fluid phase.
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