The PA Mitochondria Express Less Complex I and III Subunits but More MnSOD than the RA Mitochondria

The depolarization in mitochondria is likely a direct result of the decreased respiration, since decreased activity of the ETC would result in less H+ pumped out of the inner membrane while, at the same time, the electrons are not flowing down the ETC and are readily available to react with molecular 02 to generate more AOS. Although we did not study ETC complexes' activity, we compared the expression of specific subunits of complexes I and III and showed that, in the PA, there is, as expected, less of both complexes I and III. At the same time, MnSOD protein expression is much higher in the PA than the RA, while MnSOD mRNA expression is higher in RA than in PA (Fig. 7). This is in agreement with our previous observations since MnSOD is known to be dynamically regulated and it is upregulated when the superoxide levels are high, as it occurs in the PA. It also explains the results shown in Figure 4 where, while the superoxide levels increase with hypoxia in the kidney mitochondria, the H202 levels do not. This might be because there is inadequate level of MnSOD expression that is required for the conversion of superoxide to H202.

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Figure 7. Differences in the expression of mitochondrial proteins in PA and RA. A: Immunoblot analysis showing that the expression of complex I (NADH ubiquinol oxidoreductase, 39 kDa subunit) and III (ubiquinol cytochrome c oxidoreductase, subunit 1) in PA and RA. B: RT-PCR (a) and immunobloting (6) analysis of MnSOD in PA and RA.

The findings discussed support many of the known features of vascular 02 sensing. The high level of H202 production at baseline in the PA could explain the relatively dilated (low pressure) state of the pulmonary circulation in comparison to its systemic counterpart. Tonically produced H202 from the proximal ETC can diffuse to the cytoplasm and cause K+ channel activation, PASMC hyperpolarization, decreased opening of voltage-gated Ca2+ channels, decreased [Ca2+]; levels, and vasodilation. During acute hypoxia, the tonic production of this mitochonclrial-derived vasodilator (H202) decreases, thus promoting inhibition and vasoconstriction, i.e., hypoxic pulmonary vasoconstriction. In contrast, a hypoxia-induced increase in AOS (Fig. 4A) would increase /K (20) in renal arterial smooth muscle cells and promote RA vasodilation (Fig. 3A).

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