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PKNOX2 regulates myofibroblast functions and tubular cell survival during kidney fibrosis

Yoshiaki Miyake1, Masanori Obana2, Takafumi Nakae1

  • 1Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, Japan.

Biochemical and Biophysical Research Communications
|July 26, 2021
PubMed

Insights

The transcription factor PKNOX2 promotes kidney fibrosis by increasing myofibroblast activity and survival. Reducing PKNOX2 expression may offer a therapeutic strategy for chronic kidney disease (CKD).

Area of Science:

  • Nephrology
  • Molecular Biology
  • Cell Biology

Background:

  • Chronic kidney disease (CKD) is a growing global health concern.
  • Kidney fibrosis, a key driver of CKD progression, involves tubular cell death and (myo)fibroblast activation.
  • The precise molecular mechanisms of kidney fibrosis remain incompletely understood.

Purpose of the Study:

  • To investigate the role of the transcription factor PBX/Knotted Homeobox 2 (PKNOX2) in kidney fibrosis.
  • To elucidate the impact of PKNOX2 on (myo)fibroblast and tubular epithelial cell function during kidney injury.

Main Methods:

  • Utilized a unilateral ureteral obstruction (UUO) mouse model to induce kidney fibrosis.
  • Assessed PKNOX2 expression in kidney tissues using transcript and protein analysis.
  • Employed immunofluorescence microscopy to localize PKNOX2 expression.
  • Used shRNA lentiviral system for PKNOX2 knockdown in (myo)fibroblasts and tubular epithelial cells.
  • Investigated the effects of PKNOX2 modulation on cell viability, apoptosis, and migration.

Main Results:

  • PKNOX2 expression was significantly upregulated in fibrotic kidneys post-UUO.
  • PKNOX2 levels increased in myofibroblasts but decreased in proximal tubular epithelial cells after UUO.
  • TGF-β1 induced PKNOX2 expression in (myo)fibroblasts.
  • PKNOX2 knockdown reduced (myo)fibroblast viability, promoted apoptosis, and inhibited TGF-β1-induced migration and differentiation.
  • PKNOX2 knockdown also decreased tubular epithelial cell viability and increased apoptosis.

Conclusions:

  • PKNOX2 plays a critical role in regulating (myo)fibroblast function and survival during kidney fibrosis.
  • PKNOX2 influences the viability of proximal tubular epithelial cells, impacting kidney fibrosis progression.
  • Targeting PKNOX2 may represent a novel therapeutic approach for managing kidney fibrosis and CKD.
Keywords:
Kidney fibrosisMyofibroblastsPKNOX2Proximal tubular epithelial cells

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