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Parathyroid hormone-related protein protects renal tubuloepithelial cells from apoptosis by activating transcription

Juan A Ardura1, Ana B Sanz, Alberto Ortiz

  • 1Bone and Mineral Metabolism Laboratory, Instituto de Investigación Sanitaria (IIS)-Fundación Jiménez Díaz, and Instituto de Salud Carlos III-RETICEF RD06/0013/1002, Madrid, Spain. jaardura@fjd.es

Kidney International
|February 1, 2013
PubMed

Insights

Parathyroid hormone-related protein (PTHrP) promotes kidney tubule cell survival by activating Runx2, a key transcription factor. This pathway increases antiapoptotic proteins, protecting cells from injury and renal failure.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Cell Biology

Background:

  • Runx2 is crucial for bone development and osteoblast survival.
  • Parathyroid hormone (PTH) exerts antiapoptotic effects in osteoblasts via Runx2.
  • PTH-related protein (PTHrP) promotes kidney tubulointerstitial cell survival through the PTH/PTHrP type 1 receptor.

Purpose of the Study:

  • To investigate the role of Runx2 in renal tubuloepithelial cell survival regulated by PTHrP.
  • To determine if PTHrP-mediated cell survival in the kidney involves Runx2.
  • To explore the molecular mechanisms of PTHrP action in renal cells.

Main Methods:

  • Assessed Runx2 expression in renal cell lines (MCT, HK2) and mouse kidney tubuloepithelium.
  • Administered PTHrP(1-36) fragment to cell lines and analyzed Runx2 expression and nuclear translocation.
  • Utilized dominant-negative Runx2 constructs and Runx2 siRNA to inhibit Runx2 activity.
  • Measured expression of antiapoptotic proteins (Bcl-2, osteopontin) and assessed cell viability under stress conditions (folic acid toxicity, serum deprivation).
  • Examined Runx2, osteopontin, and Bcl-2 levels in kidneys from PTHrP transgenic mice and mice with renal failure.

Main Results:

  • Runx2 is expressed in renal tubuloepithelial cells.
  • PTHrP(1-36) significantly increased Runx2 expression and nuclear translocation in a dose- and time-dependent manner.
  • PTHrP(1-36) conferred protection against renal cell injury, which was blocked by Runx2 inhibition.
  • PTHrP(1-36) upregulated Bcl-2 and osteopontin expression, dependent on Runx2.
  • Runx2, osteopontin, and Bcl-2 were elevated in conditions of renal injury and PTHrP overexpression.

Conclusions:

  • PTHrP plays a protective role in renal tubuloepithelial cells by activating Runx2.
  • The PTHrP-Runx2 pathway upregulates prosurvival proteins like Bcl-2 and osteopontin.
  • This mechanism is relevant in the context of kidney injury and disease.

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