{
  "id": 10749800,
  "title": "Genetic Variation, Iron Status, and FGF23 Signaling Converge to Regulate Renal Calcium Buffering in Sickle Cell Disease",
  "url": "https://urgent.news/2026/09/29/genetic-variation-iron-status-and-fgf23-signaling-converge-to",
  "topic": "science",
  "section": "Science",
  "published": "2026-09-29T00:00:00.000Z",
  "source": {
    "name": "bioRxiv",
    "slug": "biorxiv",
    "url": "https://www.biorxiv.org/content/10.64898/2026.09.23.752598v1?rss=1"
  },
  "original_language": "en",
  "account": "Sickle cell disease (SCD) is associated with significant variations in mineral levels, including hypocalcemia. The kidneys play a key role in managing systemic calcium levels, reabsorbing calcium from the glomerular filtrate through both paracellular and transcellular transport pathways. However, the extent to which genetic and environmental factors influence these processes in SCD is unclear. Utilizing mouse models with SCD and single-cell multiomics, researchers have pinpointed the distal convoluted tubule (DCT) as the nephron segment most vulnerable to calcium reabsorption issues in SCD, primarily due to reduced levels of calcium buffer protein calbindin 1 (CALB1). CALB1 and its associated mRNA expression are lower in DCT cells within SCD, alongside decreased Klotho (KL)-dependent fibroblast growth factor (FGF) 23 signaling and intracellular calcium signaling. Limiting dietary iron also decreases CALB1, KL, and calcium exporter SLC8A1 levels in the kidneys of SCD patients. When CALB1 is lost, DCT cells transition to a more energy-inefficient glycolysis process, which reduces the availability of 2,3-diphosphoglycerate and hampers KL-dependent FGF23 signaling. This creates a feedback loop that suppresses calcium reabsorption. A comprehensive analysis of gene expression and protein quantitative trait loci data from kidneys of genetically varied mice has revealed that CALB1 expression levels are highly heritable and coordinated with SLC8A1, establishing a genetic mechanism that determines the kidney's ability to buffer and transport calcium towards the bloodstream. The combined evidence from these findings supports the notion that genetic variations, dietary iron status, and FGF23 signaling intersect at the DCT level to diminish renal calcium reabsorption in the kidneys of SCD patients. This convergence of factors suggests the potential for personalized, genotype- and iron-dependent treatment approaches to address mineral metabolism issues in SCD.",
  "summary": "Sickle cell disease (SCD) causes heterogeneous mineral imbalances including variable degrees of hypocalcemia. The kidney controls systemic calcium by reabsorbing calcium from the glomerular filtrate via paracellular transport and transcellular transport in the nephron tubules, yet it is unknown whether these processes are modulated by genetic or environmental factors or disrupted in SCD. Using…",
  "key_points": [],
  "editors_take": null,
  "illustration": null,
  "coverage": {
    "outlets": 1,
    "also_reported_by": []
  },
  "ai_generated": true,
  "disclaimer": "Summaries, key points and the editor’s take are written by software from other outlets’ reporting and may contain errors — always check the linked original."
}