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Protease-activated receptor 2 protects against VEGF inhibitor-induced glomerular endothelial and podocyte injury

Yuji Oe1,2, Tomofumi Fushima3, Emiko Sato3,4

  • 1Division of Feto-Maternal Medical Science, Department of Community Medical Support, Tohoku Medical Megabank Organization, Tohoku University, Sendai, 980-8574, Japan.

Scientific Reports
|March 1, 2019
PubMed

Insights

Protease-activated receptor 2 (PAR2) protects against kidney damage caused by vascular endothelial growth factor (VEGF) inhibitors. Lack of PAR2 worsens glomerular injury and podocyte damage in mice lacking endothelial nitric oxide synthase (eNOS).

Area of Science:

  • Nephrology
  • Molecular Biology
  • Immunology

Background:

  • Vascular endothelial growth factor (VEGF) inhibitors can induce glomerular injury.
  • Protease-activated receptor 2 (PAR2) activation by factor Xa has been shown to worsen diabetic kidney disease.
  • The specific role of PAR2 in VEGF inhibitor-induced glomerular injury remains unclear.

Purpose of the Study:

  • To investigate the protective role of PAR2 in glomerular injury induced by VEGF blockade.
  • To determine the effect of PAR2 deficiency on VEGF inhibitor-induced kidney damage, particularly in the context of endothelial nitric oxide synthase (eNOS) deficiency.

Main Methods:

  • Administration of an anti-VEGF antibody to wild-type mice, mice lacking PAR2, and mice lacking both PAR2 and eNOS.
  • Assessment of renal phenotype, including albuminuria and glomerular injury.
  • Evaluation of kidney tissue for expression levels of CD31, VEGF, and angiogenesis-related chemokines.
  • Histological examination for podocyte injury.

Main Results:

  • Anti-VEGF antibody alone did not cause renal phenotype in wild-type mice.
  • Anti-VEGF antibody administration induced glomerular injury in mice lacking eNOS.
  • In mice lacking both PAR2 and eNOS, anti-VEGF antibody exacerbated albuminuria and reduced CD31, VEGF, and chemokine expression.
  • Podocyte injury was observed in PAR2-deficient mice treated with anti-VEGF antibody and lacking eNOS.

Conclusions:

  • PAR2 plays a protective role against VEGF inhibitor-induced glomerular endothelial injury.
  • PAR2 deficiency exacerbates podocyte injury in the context of VEGF blockade and eNOS deficiency.
  • These findings highlight PAR2 as a potential therapeutic target for mitigating kidney damage associated with VEGF inhibition.

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