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Abstract: TH-OR40

Loss of Renal Tubular Claudin-2 Increases Renal Calcification and Urinary Stone Disease

Session Information

Category: Bone and Mineral Metabolism

  • 501 Bone and Mineral Metabolism: Basic

Authors

  • Jayachandran, Muthuvel, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, United States
  • Holmes, Heather L., Mayo Clinic College of Medicine and Science, Rochester, Minnesota, United States
  • Haskic, Zejfa, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, United States
  • Rule, Andrew D., Mayo Clinic College of Medicine and Science, Rochester, Minnesota, United States
  • Romero, Michael F., Mayo Clinic College of Medicine and Science, Rochester, Minnesota, United States
  • Koo, Kevin, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, United States
  • Lieske, John C., Mayo Clinic College of Medicine and Science, Rochester, Minnesota, United States
Background

Mechanisms of hypercalciuria-associated renal calcification and urinary stone disease (USD) are not completely understood. Global Claudin-2 knockout (Cldn2KO) male mice share many key features of human hypercalciuric idiopathic calcium stone formers (ICSFs). Here we characterized urine biochemistry, urinary extracellular vesicles (uEVs), and renal pathophysiology to determine if uEVs could serve as a biomarker for human idiopathic, hypercalciuric, first time stone formers (SFs) with potential pathologic changes in renal claudin-2 (Clnd2) expression.

Methods

Twenty-hour (24-h) urine samples were collected from male mice (Cldn2KO (n=12) and age-matched wild type (WT; n=8)) and human SFs (n=20; hypercalciuric SFs and age-/sex-matched non-SFs (NSFs). In vivo renal calcification in mice were measured by Bruker high-resolution in vivo 3D X-ray microtomography. Data are presented as median (25th, 75th percentile) and analyzed by Wilcoxon rank-sum test to identify statistically significant (P<0.05) differences between groups.

Results

Age, body weight, total 24-h urine volume, milliosmole, excretion of 24-h urine albumin, Cl-, phosphorous, K+, protein, and Na+ were not different between Cldn2KO and WT mice. However, 24-h excretion of urinary Ca2+ was greater (P<0.002; Fig.) in Cldn2KO compared to WT mice. Spontaneous renal papillary calcifications were identified in Cldn2KO (Fig.) but not WT mice. Cldn2 protein expression on uEVs was increased in SFs compared NSFs (P=0.004; Fig.).

Conclusion

Loss of renal tubular Clnd2 protein increased urinary Ca2+ excretion and papillary calcification in mice. Our nephrectomy patients study showed a significant decrease in Clnd2 expression in SFs compared NSFs. Thus, increased excretion of Cldn2 protein carrying uEVs in hypercalciuric SFs may reflect decreased tubular Cldn2 protein expression that results in reduced renal Ca2+ reabsorption and increased USD, and quantification of Clnd2 content of uEVs could serve as a useful biomarker for further studies.

Funding

  • NIDDK Support