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Kidney Week

Abstract: FR-PO967

Stat3 Activation Is Elevated in Pre-Cystic Kidneys of Thm1 Conditional Knock-out Mice

Session Information

Category: Genetic Diseases of the Kidney

  • 1001 Genetic Diseases of the Kidney: Cystic

Authors

  • Silva, Luciane M., University of Kansas Medical Center, Kansas City, Kansas, United States
  • Gunewardena, Sumedha S., University of Kansas Medical Center, Kansas City, Kansas, United States
  • Tran, Pamela Vivian, University of Kansas Medical Center, Kansas City, Kansas, United States
Background

Primary cilia are sensory organelles that mediate signaling pathways. Dysfunction of cilia leads to renal cystic disease. Multiple cellular and signaling aberrations contribute to renal cystogenesis, while the initiating molecular mechanisms remain unknown. In mice, perinatal global deletion of the ciliary gene, Thm1, causes renal cysts beginning at postnatal day (P) 15.

Methods

To identify molecular events that initiate renal cystogenesis in Thm1 conditional knockout (cko) mice, we performed RNA sequencing on kidney RNA lysates of pre-cystic P9 and cystic P42, Thm1 cko mice and control littermates. We reasoned that genes with significantly altered expression at both P9 and P42 would represent early initiation events leading to cystogenesis.

Results

Endothelin 1, Egr2, Fos, Jun, Stat3, endothelial Vcam1, immune genes, Complement C3 and Adcy7, were upregulated at P9 and further upregulated at P42. Western blot analysis showed increased P-STAT3 at P10, and upregulation of multiple components of STAT and EDN1-MAPK signaling pathways at P42. Immunohistochemistry revealed more intense nuclear localization of P-STAT3 in epithelial cells of non-dilated and dilated tubules at P20, and in cyst-lining epithelial cells and interstitial cells at P42. To study the connection between primary ciliary dysfunction and upregulated STAT3 signaling, we have generated Thm1 knock-down human renal 293T clonal cell lines. These cell lines show shortened primary cilia with IFT81 accumulation in a bulb-like structure at the distal tip, indicative of a retrograde ciliary protein trafficking defect.

Conclusion

Our data reveal upregulated Stat3 activation in pre-cystic Thm1 cko kidneys and suggest that simultaneous alteration of gene expression and signaling in renal epithelial, vascular and immune cells may potentiate renal cyst initiation. We are examining mechanisms by which Thm1-deficient cilia cause increased Stat3 activation and are inhibiting Stat3 pharmacologically in Thm1 cko mice. This may reveal initiating mechanisms underlying Thm1-deficient renal cystogenesis.

Funding

  • NIDDK Support