Abstract: TH-PO568

Overexpression of Activated TGFβ1 in Collecting Ducts Induces Cyst-Like Tubule Dilations and Renal Fibrosis in Wildtype Mice and Accelerates the Decline in Renal Function in ADPKD Mice

Session Information

Category: Genetic Diseases of the Kidney

  • 801 Cystic Kidney Diseases

Authors

  • Dai, Yuqiao, University of Kansas Medical Center, Kansas City, Kansas, United States
  • Zhang, Yan, University of Kansas Medical Center, Kansas City, Kansas, United States
  • Raman, Archana, University of Kansas Medical Center, Kansas City, Kansas, United States
  • Daniel, Emily A., University of Kansas Medical Center, Kansas City, Kansas, United States
  • Khanna, Aditi, University of Kansas Medical Center, Kansas City, Kansas, United States
  • Reif, Gail, University of Kansas Medical Center, Kansas City, Kansas, United States
  • Pierucci-Alves, Fernando, Kansas State University, Manhattan, Kansas, United States
  • Wallace, Darren P., University of Kansas Medical Center, Kansas City, Kansas, United States
Background

Transforming growth factor β1 (TGFβ1), a master regulator of extracellular matrix production, is elevated in autosomal dominant polycystic kidney disease (ADPKD). TGFβ1 is also elevated in Marfan Syndrome (MFS), a genetic disorder leading to abnormal connective tissue development, defects in multiple organs, and formation of renal cysts in approximately 60% of patients. Currently, the role of activated TGFβ1 in renal cyst formation in MFS and the effect of TGFβ1 on cyst growth and disease progression in ADPKD remain unclear.

Methods

To determine if activated TGFβ1 is sufficient to induce renal cyst formation and fibrosis, we crossed β1glo (TGFβ1) mice, which conditionally express TGFβ1, with Pkhd1-Cre mice to express activated TGFβ1 selectively in collecting ducts (CD; TGFβ1CD). We also overexpressed activated TGFβ1 in CDs of Pkd1RC/RC mice, a slowly progressive model of ADPKD.

Results

CD overexpression of TGFβ1 caused cyst-like tubule dilations and increased kidney weight (% body weight; KW%BW) by 5 wk of age. However, by 10 wk, the kidneys developed focal area of fibrosis and pitting of the surface that was indicative of scarring, and there was a significant reduction in KW%BW of TGFβ1CD mice compared to wildtype (WT) mice. There were increased renal levels of periostin, a marker for PKD progression, phosphorylated SMAD3, α-smooth muscle actin (α-SMA) and vimentin, markers for myofibroblasts. Blood urea nitrogen (BUN) was slightly increased in TGFβ1CD mice compared to WT mice at 20 wk, but this difference was not statistically significant. Similar results were obtained in Pkd1RC/+ mice, which have one hypomorphic Pkd1 allele. Overexpression of TGFβ1 in Pkd1RC/RC mice did not increase cystic index, but rather caused extensive fibrosis and contraction of the kidneys, leading to decreased KW%BW. This was accompanied by increased levels of periostin, α-SMA and vimentin, and a decline in renal function, evidenced by an elevation of BUN compared to Pkd1RC/RC mice.

Conclusion

Our results demonstrate that expression of activated TGFβ1 is sufficient to induce cyst-like tubule dilations and renal fibrosis in normal mice, and accelerate the decline in kidney function in ADPKD mice.
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Funding

  • NIDDK Support