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Kidney Week

Abstract: FR-PO958

Protection Effect of Klotho on Cyst Growth in Autosomal Dominant Polycystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidney

  • 1001 Genetic Diseases of the Kidney: Cystic

Authors

  • Li, Xiaoyan, University of Kansas Medical Center, Kansas City, Kansas, United States
  • Bu, Lei, University of Kansas Medical Center, Kansas City, Kansas, United States
  • Lyu, Jiayi, University of Kansas Medical Center, Kansas City, Kansas, United States
  • Zhou, Xia, University of Kansas Medical Center, Kansas City, Kansas, United States
  • Agborbesong, Ewud, University of Kansas Medical Center, Kansas City, Kansas, United States
  • Li, Xiaogang, University of Kansas Medical Center, Kansas City, Kansas, United States
Background

ADPKD is the most common hereditary renal disorder. Klotho is a protein with a single transmembrane domain, which is mainly expressed in the kidney and acts as a co-receptor for fibroblast growth factor 23 (FGF23). The membrane bound extracellular domain of Klotho (soluble α-Klotho) can be cleaved and released into the blood stream. The soluble a-Klotho levels in ADPKD patients was decreased. However, the mechanisms for the downregulation of Klothos and its roles in regulating cyst development remain unknown.

Methods

To evaluate a potential role of Klotho in cyst pathophysiology, we investigated the expression of Klotho in cystic kidneys from ADPKD patients and Pkd1flox/flox conditional knockout mice by using immunohistochemistry staining, western blot and qRT-PCR. A recombinant mouse Klotho was used to evaluate its effects on cyst growth in vivo.

Results

We found that the expression of Klotho in the kidneys from ADPKD patients and Pkd1 knockout mice was decreased in addition to the decrease of the soluble a-Klotho levels in the serum of ADPKD patients. We further found that the methylation on the promoter of Klotho was increased in the genome of ADPKD patients and Pkd1 mutant mice, which provided a mechanism for the downregulation of Klothos in ADPKD by the upregulated DNA methyltransferases (DNMTs). Treatment with the recombinant mouse Klotho delayed cyst growth as seen by decreased cystic index, kidney weight (KW)/body weight (BW) ratios, blood urea nitrogen (BUN) levels, cyst lining epithelial cell proliferation, and increased cyst lining epithelial cell apoptosis in Pkd1 mutant mice (all p < 0.01). Klotho treatment decreased the activation and phosphorylation of Akt, ERK, Rb, S6, and STAT3, whereas it increased the expression of p21. Since Klotho overexpression mice is normal and the average lifespan is about 20-30% longer that the wild type mice, overexpression or treatment with Klotho should not only protect renal function but also has less side effect.

Conclusion

The expression of Klotho was not only deceased in the serum of ADPKD patients but also in the kidneys from ADPKD patient and Pkd1 knockout mice, which was regulated by the DNMTs mediated methylation on the promoter of Klotho. Treatment with the recombinant Klotho may be a viable new therapy for ADPKD.

Funding

  • NIDDK Support