Abstract 060: POLDIP-2/NOX-4 Generates Hydrogen Peroxide that Impairs Myogenic Response of Afferent Arterioles from Mice with the Reduced Renal Mass Model of Chronic Kidney Disease
Background: Because we have found that myogenic contractions are stimulated by superoxide (O2.-) but inhibited by hydrogen peroxide (H2O2), we tested the hypothesis that H2O2 is the cause of the impaired myogenic responses of afferent arterioles from mice with the reduced renal mass (RRM) model of chronic kidney disease (CKD).
Methods: Mice were subjected to 5/6 surgical nephrectomy or sham operations and fed 6% salt for 3 months. Single afferent arterioles were perfused, their diameter measured directly and O2.- and H2O2 measured by fluorescence microscopy.
Results: The perfusion pressure of isolated afferent arterioles was increased from 40 to 80 mmHg to study myogenic responses. Arterioles from mice with RRM (vs sham) had a greater increase in O2.- (21.2 ± 1.9 versus 11.3 ± 2.5%; p < 0.01) and especially H2O2 (28.7 ± 3.7 versus 4.2 ± 0.4%, P<0.005), but a reduction in myogenic contraction (-1.7 ± 4.3 versus -14.4 ± 3.6%; p < 0.005) . Myogenic contractions were paradoxically reversed in afferent arterioles from mice with RRM after reduction in O2.- by PEG-SOD (+3.3 ± 1.5 versus -1.7 ± 4.3%, P<0.05) or deletion of p47phox (+2.5 ± 1.4 versus -1.7 ± 4.3%, P<0.05). In contrast, myogenic responses were increased even above the levels of shams in arterioles from mice with RRM after reduction in H2O2 by PEG-catalase (-19.1 ± 1.6 versus -1.7 ± 4.3%, P<0.005) or transgenic overexpression of catalase in smooth muscle cells (-10.7 ± 1.3 versus -1.7 ± 4.3%, P<0.01). Gene expression for NOX-4 and POLDIP-2 (main source of H2O2) was increased 40-50% (P<0.05) in individual afferent arterioles from mice with RRM. Moreover, the myogenic contractions in the arterioles from POLDIP-2+/- mice with RRM were similar to POLDIP-2+/- with sham operations (-7.7 ± 0.9 versus -8.0 ± 0.6, P=NS).
Conclusions: Afferent arterioles from mice with RRM had severely impaired myogenic responses that were attributed to increased H2O2 generation from POLDIP-2/NOX-4 that may therefore be novel targets to maintain autoregulation and protect kidneys from barotrauma in CKD.
Author Disclosures: L. Li: None. E. Lai: None. Z. Luo: None. G. Solis: None. K.K. Griendling: None. W. Taylor: None. W.J. Welch: None. W.S. Christopher: None.
- © 2015 by American Heart Association, Inc.