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Abstract: SA-PO099

Claudin-4, a Core Component of the Tight-Junctional Complex Along the Collecting System, Is Induced in Nephrotic Syndrome

Session Information

  • AKI: Mechanisms - III
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Sassi, Ali, Department of Cell Physiology & Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
  • Olivier, Valerie, Department of Cell Physiology & Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
  • Arnoux, Gregoire, Department of Cell Physiology & Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
  • Roth, Isabelle, Department of Cell Physiology & Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
  • Chassot, Alexandra, Department of Cell Physiology & Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
  • Feraille, Eric, Department of Cell Physiology & Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
  • Ramakrishnan, Suresh, Department of Cell Physiology & Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland

Group or Team Name

  • Department of Cell Physiology & Metabolism, Faculty of Medicine
Background

Nephrotic syndrome (NS) is characterized by massive proteinuria, hypoalbuminemia and edema secondary to renal sodium chloride retention. Along the kidney tubule, sodium and chloride reabsorption are coupled via a combination of transcellular and paracellular transport pathways. The mechanism of sodium retention in NS has been extensively studied, but the associated chloride transport pathway has not been elucidated.

Methods

To investigate the pathway of chloride retention in NS, we assessed the expression levels of both paracellular and transcellular components of chloride transport in the CD of POD-ATTAC mice and PAN rats, two rodent models of NS. We also used cultured mouse cortical collecting duct cells to see how overexpression or silencing of claudin-4 affect paracellular permeability. Finally, human renal biopsies were used to confirm our in vivo results.

Results

In control animals, claudin-4 was expressed at low levels in collecting duct (CD). In POD-ATTAC mice and PAN rats, claudin-4 expression was strongly increased in CD beta-intercalated cells (B-IC) and to a lesser extent in CD principal cells and was also induced in connecting tubules. Similarly, we found that claudin-4 was expressed at low levels in normal human kidneys and was dramatically increased in CD cells of nephrotic human kidneys (focal and segmental glomerulosclerosis). In parallel, the expression of pendrin, which exchanges chloride for bicarbonates in B-IC, was decreased in nephrotic compared to control animals. However, the increase in claudin-4 expression observed in NS is likely independent of pendrin abundance. Increased claudin-4 abundance is coupled with increased ENaC-dependent sodium transport. Overexpression or silencing of claudin-4 in mCCDcl1 cells confirmed the preferential permeability of claudin-4 to chloride over sodium.

Conclusion

These results suggest that during NS, transcellular Cl-/HCO3- transport decreases while paracellular chloride transport via claudin-4 may increase along the collecting system. Paracellular chloride permeability may constitute a chloride shunt that favors Na+ reabsorption and opposes K+ secretion along the CD in NS.

Funding

  • Government Support – Non-U.S.