Background: Impaired autoregulation and systemic hypertension underlie progressive kidney injury in chronic kidney disease (CKD). We reported that the myogenic response (MR) was severely impaired in afferent arterioles (Affs) from mice with reduced renal mass (RRM) and oxidative stress, yet superoxide (O2.-) enhanced MRs of normal mice. Therefore, we tested the hypothesis that an increase in perfusion pressure (PP) enhances the generation of H2O2 selectively in Affs from mice with RRM and that H2O2 causes the impaired MR.
Methods and Results: Groups of sham and RRM C57BL/6 mice were fed a high salt (6% NaCl) diet for 3 months. Alternative groups were treated with 2 mM of the redox cycling nitroxide tempol in drinking water for 3 months, which reduced the excretion of both 8-isoprostane (marker of O2.-) and H2O2. MRs were assessed from the % change in luminal diameter of isolated, perfused Affs after increasing PP from 40 to 80 mmHg, O2.- from PEG-SOD inhibitable ethidium:dihydroethidium fluorescence and H2O2 from PEG-catalase (CAT) inhibitable H2DCFDA fluorescence.
Results: 1. Compared to sham, increasing PP in Affs from RRM mice increased O2.- more (21 ± 2% vs 11 ± 2%, P<0.01), but this was prevented by tempol, and increased H2O2 more (29 ± 8% vs 4 ± 1%, P<0.01), which also was prevented by tempol. 2. Compared to sham, Affs from mice with RRM mice had severely impaired MRs (sham, -14 ± 4% vs RRM, -1 ± 4%, P<0.05), yet this defect was corrected in mice drinking tempol (sham + tempol, -9 ± 6% vs RRM + tempol, -11 ± 2%, NS). 3. Bath addition of PEG-SOD (200 units/ml) attenuated MRs from sham mice (sham + vehicle, -14 ± 4%; sham + SOD, -6 ± 1%; P<0.05), but did not affect responses in RRM mice. 4. Bath addition of PEG-CAT (1000 units/ml) selectively enhanced the MRs in RRM mice (RRM + vehicle -1 ± 4%; RRM + CAT -19 ± 2%; P< 0.01) without effect in sham mice (sham + vehicle, -14 ± 4%; sham + PEG-CAT, -14 ± 2% NS).
Conclusions: Excessive H2O2 is released by increased PP of the afferent arterioles only from mice with RRM and accounted for the impaired myogenic response. Tempol, or other drugs that metabolize H2O2, may preserve renal autoregulation and prevent progressive loss of GFR in CKD.