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Kidney Week

Abstract: SA-PO817

Regulation of Klotho by Proteinuria in CKD

Session Information

Category: CKD (Non-Dialysis)

  • 1903 CKD (Non-Dialysis): Mechanisms

Authors

  • Delitsikou, Vasiliki, Faculty of Medicine, University of Geneva, Geneva, Switzerland
  • Ino, Frederique, Faculty of Medicine, University of Geneva, Geneva, Switzerland
  • Jarad, George, Washington University School of Medicine, St. Louis, Missouri, United States
  • Miner, Jeffrey H., Washington University School of Medicine, St. Louis, Missouri, United States
  • De Seigneux, Sophie M., Faculty of Medicine, University of Geneva, Geneva, Switzerland
Background

Albuminuria, caused by lesions in the glomerular filtration barrier, promotes tubular inflammation, apoptosis and fibrosis in Chronic Kidney Disease (CKD). Previously, it was shown that albuminuria is associated with lower Klotho levels. Our aim is to further investigate how albuminuria regulates Klotho expression.

Methods

Transgenic mice with inducible podocyte apoptosis (POD-ATTAC) were used, as well as Alport mice, either wild type or deficient in albumin. For the in vitro experiments, HEK cells overexpressing the human transmembrane form of Klotho and HK-2 cells were used.

Results

In vivo in POD-ATTAC mice, 3 and 7 days after podocyte loss, both Klotho mRNA and protein levels were downregulated without modifications of ADAMs activities and expression. In vitro, upon BSA treatment, the total and membrane fractions of the Klotho protein were decreased while Klotho protein half-life was also significantly reduced. Cleaved Klotho as measured in the supernatant was decreased proportionally, arguing against enhanced cleavage. Likewise, a reduction of Klotho mRNA and protein levels was observed in HK-2 cells. In the Alport mice, Klotho expression was decreased as measured by qPCR and Western blot. However, this was not the case in the Alport albumin deficient mice, implying some specificity of the regulation by albuminuria itself and not only by the primary renal disease. Similarly, there was no Klotho downregulation upon exposure to immunoglobulins in vitro. In vivo and in vitro, albuminuria induced some features of ER stress. Inhibition of ER stress increased Klotho protein levels in vitro and in vivo, suggesting that this mechanism may participate to the enhanced Klotho degradation by albuminuria.

Conclusion

In conclusion, albuminuria has a specific role on Klotho downregulation in vitro and in vivo that seems to depend on ER stress induction.