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Up-regulation of Cks1 and Skp2 with TNFα/NF-κB signaling in chronic progressive nephropathy

Sayuri Suzuki1, Hirotaka Fukasawa, Taro Misaki

  • 1Department of Biochemistry 1, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan.

Genes to Cells : Devoted to Molecular & Cellular Mechanisms
|October 25, 2011
PubMed

Insights

Skp2 and Cks1, key proteins in p27 regulation, increase during kidney damage. Their upregulation by TNFα and NF-κB pathways contributes to p27 reduction and chronic nephropathy progression.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Cellular Biology

Background:

  • The cyclin-dependent kinase (CDK) inhibitor p27 is crucial in renal damage progression.
  • Skp2, a component of the SCF-ubiquitin ligase targeting p27, was previously found to be elevated in mouse kidney obstruction models.

Purpose of the Study:

  • To investigate the roles of Skp2 and its cofactor Cks1 in anti-thymocyte serum (ATS) rat nephropathy.
  • To elucidate the molecular mechanisms, including the involvement of TNFα and NF-κB, in the regulation of Skp2 and Cks1 during chronic kidney disease.

Main Methods:

  • Induction of anti-thymocyte serum (ATS) nephropathy in rats.
  • Immunohistochemical analysis of Skp2, Cks1, Ki67, p27, RelB, and p52 in kidney tissues.
  • In vitro studies using NRK cell line to assess TNFα's role in Skp2 and Cks1 expression.

Main Results:

  • Both Skp2 and Cks1 levels were increased in the ATS rat nephropathy model.
  • Elevated Skp2 and Cks1 correlated with increased proliferation (Ki67) and transient decrease in p27 in tubular epithelial cells.
  • TNFα mediated the expression of Skp2 and Cks1, and NF-κB subunits (RelB, p52) were involved in their upregulation.

Conclusions:

  • Skp2 and Cks1 are upregulated in early stages of renal damage via the TNFα-RelB/p52 pathway.
  • These proteins collaboratively contribute to p27 downregulation, leading to proliferative tubular dilation and chronic nephropathy progression.

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