Kidney Week

Abstract: PO1591

Klotho Improves Renal Function in Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD-UMOD)

Session Information

• Genetic Diseases of the Kidneys: Non-Cystic - 1
  October 22, 2020 | Location: On-Demand
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

• Zhang, Jing T., University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, United States

Jing T. Zhang,

• Nie, Mingzhu, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, United States

Mingzhu Nie,

• Gattineni, Jyothsna, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, United States

Jyothsna Gattineni,

• Kemter, Elisabeth, Ludwig-Maximilians-Universitat Munchen, Munchen, Bayern, Germany

Elisabeth Kemter,

• Froehlich, Thomas, Ludwig-Maximilians-Universitat Munchen, Munchen, Bayern, Germany

Thomas Froehlich,

• Wolf, Matthias Tilmann, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, United States

Matthias Tilmann Wolf,

Background

Heterozygous Uromodulin (UMOD) mutations cause ADTKD but no therapies are available. We tested if Klotho improves renal function in a murine model for ADTKD-UMOD.

Methods

To generate a stronger phenotype we crossed homozygous mutant Umod (Umod^C93F/C93F) mice with Klotho-overexpressing (TgKl) mice. We studied wild-type (WT), TgKl, Umod^C93F/C93F and TgKl/Umod^C93F/C93F mice at 6 and 13 months. For quantitative proteome analysis (LC-MS/MS) we harvested kidneys at 3 months.

Results

1. Compared to Umod^C93F/C93F mice, TgKl/Umod^C93F/C93F animals had significantly lower serum BUN, creatinine, cystatin C (see Figure 1), PTH, FGF23 values, and less renal fibrosis.
2. Mutant UMOD is retained in the endoplasmic reticulum but relative urinary UMOD secretion was higher in TgKl/Umod^C93F/C93F vs. Umod^C93F/C93F (relative UMOD protein expression 0.27±0.15 vs 0.13±0.06, p<0.05).
3. Compared to Umod^C93F/C93F, TgKl/Umod^C93F/C93F animals had significantly lower systolic (mean 118±5 vs. 137±5 mmHg, p<0.05) and diastolic blood pressures (56±4 vs. 83±7 mmHg, p<0.01), and lower mRNA expression of markers of cardiac hypertrophy.
4. To identify the mechanism for better renal outcome in TgKl/Umod^C93F/C93F, we performed an unbiased proteomics approach. We identified downregulation of Transforming growth factor-beta-induced protein (TGFBI) together with multiple collagens, prolargin, biglycan, and osteoglycin/mimecan in TgKl/Umod^C93F/C93F vs. Umod^C93F/C93F animals. We confirmed lower mRNA expression of TGFBI and collagens.

Conclusion

Klotho improves renal outcome in ADTKD-UMOD mice by increasing urinary UMOD secretion and ameliorating renal fibrosis by downregulation of TGFBI and collagens.

TgKl/Umod^C93F/C93F mice show significantly lower BUN, creatinine, and cystatin C values.

Funding

• NIDDK Support