Kidney Week

Abstract: TH-PO0130

Defective Tubular Albumin Reabsorption in CUBN Variants Disrupts Tubuloglomerular Feedback and Promotes Hyperfiltration Injury

Session Information

• Integrative Genomics and Multi-Omics in Noncystic Genetic Kidney Disease
  October 22, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1202 Genetic Diseases of the Kidneys: Non-Cystic (Complex and Non-Cystic Monogenic)

Author

• Rao, Jia, Shanghai Jiaotong University School of Medicine Xinhua Hospital, Shanghai, China

Jia Rao

Background

Biallelic variants in CUBN, encoding the proximal tubular albumin receptor cubilin, are increasingly recognized as causes of proteinuric kidney disease. However, how defective tubular albumin reabsorption influences renal hemodynamics and susceptibility to kidney injury remains poorly understood.

Methods

To elucidate the pathogenic mechanisms of biallelic CUBN variants and determine how cubilin deficiency affects tubular–glomerular crosstalk and kidney injury progression. Whole-exome sequencing was performed in families with steroid-resistant nephrotic syndrome or proteinuric kidney disease. Functional consequences of a deep intronic variant were assessed using minigene splicing assays. Renal biopsy specimens were analyzed by immunohistochemistry and immunofluorescence. A Cubn^c.6821+3A>G point mutation mouse was generated using semi-cloning technology. Renal phenotypes were evaluated under basal conditions and in lipopolysaccharide-induced acute kidney injury and Adriamycin-induced chronic kidney disease models. Primary proximal tubular epithelial cells were used to assess albumin uptake and albumin-induced cellular injury in vitro.

Results

We identified 23 novel pathogenic CUBN variants in 21 individuals, who exhibited chronic proteinuria with preserved renal function. Renal biopsies showed loss of cubilin brush border localization, mislocalization of cubilin and amnionless, and reduced megalin expression. Cubn mutant mice developed marked albuminuria with normal serum albumin and creatinine levels and predominantly tubular injury at baseline. Under stress conditions, mutant mice displayed exaggerated albuminuria, tubular damage, interstitial fibrosis, and glomerular injury. Mechanistically, cubilin deficiency was associated with increased macula densa nNOS and tubular COX-2 expression, indicating dysregulated tubuloglomerular feedback and hyperfiltration-associated injury. In contrast, cubilin-deficient proximal tubular cells showed impaired albumin endocytosis and reduced susceptibility to albumin overload–induced cytotoxicity in vitro.

Conclusion

Biallelic CUBN variants cause tubular proteinuria with initially preserved glomerular function but promote hyperfiltration-driven kidney injury through dysregulated tubuloglomerular feedback. Cubilin plays a critical role in coordinating tubular albumin handling and glomerular homeostasis.