Protein kinase C inhibitor prevents renal apoptotic and fibrotic changes in response to partial ureteric obstruction

Authors


  • Y.-S. J. and S.-M. C. contributed equally to the work.

Chun-Hsiung Huang, Department of Urology, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung City 807, Taiwan. e-mail: chhuang@kmu.edu.tw

Abstract

What's known on the subject? and What does the study add?

Protein kinase C inhibitor (PKCI) can decrease glomerular and tubular cell apoptosis and mitosis and attenuate collagen accumulation and fibronectin expression in a PUUO rat model.

Although the role of PKC has been well studied in diabetic nephropathy, there is no report on its role in obstructive nephropathy. This investigation evaluated the processes that were associated with the activation of PKCα and PKCβ pathways and showed that PKCI played an important role in the protection of renal function during ureteric obstruction.

OBJECTIVES

  • • To investigate the expression of the protein kinase C (PKC) pathway after partial unilateral ureteric obstruction (PUUO).
  • • To evaluate the therapeutic potential of a PKC inhibitor (PKCI) in obstructive nephropathy.

MATERIALS AND METHODS

  • • Thirty-six rats were divided into three groups. One sham-operated group served as the control. The other two groups received PUUO surgery, after which one group received no treatment and the other group was treated with PKCI, chelerythrine.
  • • The severity of hydronephrosis and renal morphology were assessed: tubular and glomerularcell apoptosis, mitosis and interstitial fibrosis were examined using immunohistochemistry.
  • • Western immunoblots were performed to determine fibronectin, transforming growth factor-β (TGF-β), and PKC isoform levels.

RESULTS

  • • Two weeks after PUUO surgery, hydronephrosis progressively developed. Tubular-interstitial fibrosis, collagen deposition and fibronectin expression were increased.
  • • PUUO also activated the expression of PKCα and PKCβ and the translocation of PKCs from cell cytosol to cell membranes.
  • • Treatment with PKCI significantly decreased PKCα and PKCβ expression and translocation in the renal cortex.
  • • Treatment with PKCI also reduced the severity of hydronephrosis, decreased both glomerular and tubular cell apoptosis and mitosis, and attenuated the collagen and fibronectin accumulation in renal interstitium.

CONCLUSIONS

  • • Renal tubular apoptosis and interstitial fibrosis after obstructive nephropathy are associated with PKCα and PKCβ activation.
  • • The PKCI, chelerythrine, is capable of decreasing PKC expression and translocation in the renal cortex, suggesting that this inhibitor may have therapeutic potential in the protection of renal function in the first few weeks after PUUO surgery.

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