ArticleAmerican journal of physiology. Cell physiology2017
Hemoglobin inhibits albumin uptake by proximal tubule cells: implications for sickle cell disease.
Article in American journal of physiology. Cell physiology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers, 1 of them a synthesis that pooled it.
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Who cites it
20 citing papers in PubMed, 1 synthesis or guideline pooled it, 33 citations in OpenAlex.
- Systematic Review of Genetic Modifiers Associated with the Development and/or Progression of Nephropathy in Patients with Sickle Cell Disease.International journal of molecular sciences · 2024Pooled it
- Tubular dysfunction in stable adult sickle cell patients in Kinshasa: prevalence and associated factors - a cross-sectional study.Renal failure · 2026Article
- Review
- Repeated aminoglycoside exposure activates interferon-stimulated genes in human renal proximal tubular models.Archives of toxicology · 2026Article
- Sex-specific glomerular filtration rate changes in response to acute hemoglobin exposure.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2025Article
- Iron Metabolism and Inflammatory Mediators in Patients with Renal Dysfunction.International journal of molecular sciences · 2024Review
- Natural history and variability in albuminuria in pediatric and murine sickle cell anemia.Blood advances · 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
- Renal outcomes in pediatric patients with sickle cell disease: a single center experience in Saudi Arabia.Frontiers in pediatrics · 2023Article
- Sickle cell nephropathy: insights into the pediatric population.Pediatric nephrology (Berlin, Germany) · 2022Review
- Biomarkers of sickle cell nephropathy in Senegal.PloS one · 2022Article
- Renal Handling of Albumin-From Early Findings to Current Concepts.International journal of molecular sciences · 2021Review
- Complement Inhibition Therapy and Dialytic Strategies in Paroxysmal Nocturnal Hemoglobinuria: The Nephrologist's Opinion.Journal of clinical medicine · 2020Review
- End points for sickle cell disease clinical trials: renal and cardiopulmonary, cure, and low-resource settings.Blood advances · 2019Article
- Hemoglobin alters vitamin carrier uptake and vitamin D metabolism in proximal tubule cells: implications for sickle cell disease.American journal of physiology. Cell physiology · 2019Article
- Mechanisms of haemolysis-induced kidney injury.Nature reviews. Nephrology · 2019Review
- Extracellular Heme Proteins Influence Bovine Myosatellite Cell Proliferation and the Color of Cell-Based Meat.Foods (Basel, Switzerland) · 2019Article
- Endogenous hepcidin synthesis protects the distal nephron against hemin and hemoglobin mediated necroptosis.Cell death & disease · 2018Article
- Chronic organ failure in adult sickle cell disease.Hematology. American Society of Hematology. Education Program · 2017Review
- The spectrum of sickle hemoglobin-related nephropathy: from sickle cell disease to sickle trait.Expert review of hematology · 2017Review
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Proximal tubule (PT) dysfunction, including tubular proteinuria, is a significant complication in young sickle cell disease (SCD) that can eventually lead to chronic kidney disease. Hemoglobin (Hb) dimers released from red blood cells upon hemolysis are filtered into the kidney and internalized by megalin/cubilin receptors into PT cells. The PT is especially sensitive to heme toxicity, and tubular dysfunction in SCD is thought to result from prolonged exposure to filtered Hb. Here we show that concentrations of Hb predicted to enter the tubule lumen during hemolytic crisis competitively inhibit the uptake of another megalin/cubilin ligand (albumin) by PT cells. These effects were independent of heme reduction state. The Glu7Val mutant of Hb that causes SCD was equally effective at inhibiting albumin uptake compared with wild-type Hb. Addition of the Hb scavenger haptoglobin (Hpt) restored albumin uptake in the presence of Hb, suggesting that Hpt binding to the Hb αβ dimer-dimer interface interferes with Hb binding to megalin/cubilin. BLAST searches and structural modeling analyses revealed regions of similarity between Hb and albumin that map to this region and may represent sites of Hb interaction with megalin/cubilin. Our studies suggest that impaired endocytosis of megalin/cubilin ligands, rather than heme toxicity, may be the cause of tubular proteinuria in SCD patients. Additionally, loss of these filtered proteins into the urine may contribute to the extra-renal pathogenesis of SCD.
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Registered trials
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