Oxidative Stress increases Pulmonary Vascular Permeability in Diabetic Rats through Activation of Transient Receptor Potential Melastatin 2 Channels

Objective In vitro superoxide activates pulmonary endothelial TRPM 2 channels and increases K f . We hypothesized that pulmonary capillary K f is increased in a model of type I diabetes due to elevated vascular superoxide and resultant TRPM 2 channel activation. Methods Type I diabetes was induced in Zucker rats using STZ. Half of the STZ animals were treated with apocynin, a NOX inhibitor. After four weeks, lung K f was measured in the isolated lung in the presence or absence of TRPM 2 inhibitors (2‐ APB and FA). In an additional set of experiments, K f was measured in nondiabetic Zucker rats after applying the superoxide donor ( PMS ). Results As compared to control rats, hyperglycemic rats exhibited increased vascular superoxide and K f , along with decreased lung vascular TRPM 2‐L expression. Apocynin treatment reduced superoxide and K f in hyperglycemic rats with no effect in control rats. TRPM 2 channel inhibition decreased K f in hyperglycemic rats with no effect in control rats. PMS increased the lung K f in control rats, with TRPM 2 inhibition attenuating this response. Conclusion Diabetic rats exhibit a TRPM 2‐mediated increase in lung K f , which is associated with increased TRPM 2 activation and increased vascular superoxide levels.