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Angiotensin II induces DNA damage via AT1 receptor and NADPH oxidase isoform Nox4

Gholamreza Fazeli1, Helga Stopper, Reinhard Schinzel

  • 1Institute of Pharmacology and Toxicology, Versbacher Str. 9, University of Würzburg, 97078 Würzburg, Germany.

Mutagenesis
|July 31, 2012
PubMed

Insights

Angiotensin II (Ang II) causes DNA damage in kidney cells through reactive oxygen species (ROS) production. This genotoxicity involves the Angiotensin II type 1 receptor (AT1R) and the NADPH oxidase 4 (Nox4) subunit.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Genetics

Background:

  • Hypertension is linked to increased renal cancer risk and mortality.
  • The renin-angiotensin-aldosterone system's activation generates reactive oxygen species (ROS).
  • Angiotensin II (Ang II) demonstrates DNA-damaging potential in renal cells.

Purpose of the Study:

  • To investigate the specific pathway through which Ang II induces genotoxicity in kidney cells.
  • To identify the molecular players involved in Ang II-mediated DNA damage.
  • To elucidate the role of NADPH oxidase isoforms in Ang II-induced renal cell damage.

Main Methods:

  • Utilized kidney cell lines with proximal tubule cell properties.
  • Investigated the roles of Angiotensin II type 1 receptor (AT1R), Gαq/11, phospholipase C (PLC), protein kinase C (PKC), and calcium signaling.
  • Assessed DNA damage via strand breaks and micronuclei induction.
  • Examined NADPH oxidase isoforms (Nox2, Nox4) using small-interfering RNA down-regulation.

Main Results:

  • Ang II activated NADPH oxidase, leading to ROS production, DNA strand breaks, and micronuclei induction.
  • The Angiotensin II type 1 receptor (AT1R) and Gαq/11 mediated this DNA damage.
  • Activation of PLC, increased intracellular calcium, and PKC were downstream events.
  • The NADPH oxidase isoform containing the Nox4 subunit, not Nox2, was responsible for Ang II's genotoxicity.

Conclusions:

  • Ang II induces DNA damage in kidney cells via AT1R-mediated activation of NADPH oxidase, specifically the Nox4 subunit.
  • The pathway involves PLC, PKC, and calcium signaling, highlighting a mechanism for hypertension-related renal damage.
  • Understanding this pathway offers potential targets for preventing renal cancer in hypertensive individuals.

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