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. 2014 Nov;21(8):754-60.
doi: 10.1111/micc.12158.

Oxidative stress increases pulmonary vascular permeability in diabetic rats through activation of transient receptor potential melastatin 2 channels

Silu Lu  1 , Lusha Xiang, John S Clemmer, Peter N Mittwede, Robert L Hester
Affiliations

Oxidative stress increases pulmonary vascular permeability in diabetic rats through activation of transient receptor potential melastatin 2 channels

Silu Lu et al. Microcirculation. 2014 Nov.

Abstract

Objective: In vitro superoxide activates pulmonary endothelial TRPM2 channels and increases Kf . We hypothesized that pulmonary capillary Kf is increased in a model of type I diabetes due to elevated vascular superoxide and resultant TRPM2 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 Kf was measured in the isolated lung in the presence or absence of TRPM2 inhibitors (2-APB and FA). In an additional set of experiments, Kf 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 Kf , along with decreased lung vascular TRPM2-L expression. Apocynin treatment reduced superoxide and Kf in hyperglycemic rats with no effect in control rats. TRPM2 channel inhibition decreased Kf in hyperglycemic rats with no effect in control rats. PMS increased the lung Kf in control rats, with TRPM2 inhibition attenuating this response.

Conclusion: Diabetic rats exhibit a TRPM2-mediated increase in lung Kf , which is associated with increased TRPM2 activation and increased vascular superoxide levels.

Keywords: TRPM2; hyperglycemia; lung permeability; superoxide.

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Figures

Figure 1
Figure 1. Pulmonary arterial TRPM2-L channel expression in control LZ and STZ-treated LZ
TRPM2-L channel is down-expressed in STZ-treated type I diabetic LZ (*, p<0.05 vs. Control). n=6 in Control LZ; n=6 in STZ-treated LZ.
Figure 2
Figure 2. Aortic superoxide levels and pulmonary arterial NADPH oxidase activity in LZ with and without STZ/apocynin treatment
A) The top is the example of confocal images obtained using a confocal microscopy from DHE-treated aorta. STZ treatment significantly increases superoxide level in aorta compared with control group (*, p<0.05 vs. control). Apocynin treatment partially normalizes superoxide in STZ-treated group (*, p<0.05 vs. control; #, p<0.05 vs. STZ group). n=6 for control group, n=5 for STZ group, n=6 for STZ+apocynin group. B) STZ treatment significantly increases NOX activity in pulmonary arteries compared with control group (*, p<0.05 vs. control). Apocynin treatment partially normalizes NOX activity in STZ-treated group (*, p<0.05 vs. control; #, p<0.05 vs. STZ group). n=6 for control group, n=6 for STZ group, n=6 for STZ+apocynin group.
Figure 3
Figure 3. Pulmonary capillary Kf in control, STZ-treated, and STZ+apocynin-treated LZ with and without 2-APB application
STZ treatment significantly increase Kf compared with control group (*, p<0.05 vs. control). Apocynin treatment partially normalizes Kf in STZ-treated group (*, p<0.05 vs. control; #, p<0.05 vs. STZ group).2-APB (1 μM) has no effect on control group, but partially normalizes Kf in STZ group (*, p<0.05 vs. 2-APB-treated control; ^, p<0.05 vs. STZ group), and in STZ+apocynin group (*, p<0.05 vs. 2-APB-treated control; ^, p<0.05 vs. STZ+apocynin group). n=5 for control, n=5 for 2-APB-treated control, n=5 for STZ, n=5 for 2-APB-treated STZ, n=6 for STZ+apocynin, n=6 for 2-APB-treated STZ+apocynin.
Figure 4
Figure 4. Pulmonary capillary Kf in control and PMS-treated LZ with and without 2-APB or FA application
PMS significantly increases Kf in LZ (*, p<0.05 vs. control LZ). 2-APB (1 μM) has no effect on control LZ but normalized Kf in PMS-treated group (#, p<0.05 vs. PMS-treated LZ). Similarly, FA (100 μM) has no effect on control LZ but partially normalized Kf in PMS-treated group (#, p<0.05 vs. PMS-treated group; *, p<0.05 vs. control LZ treated with FA). n=5 in all groups.
Figure 5
Figure 5. Pulmonary capillary Kf in PMS-treated group with and without SKF application
SKF (1 μM) has no effect on Kf in PMS-treated lungs. n=5 in all groups.
See this image and copyright information in PMC

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