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. 2008 Dec;52(6):1091-8.
doi: 10.1161/HYPERTENSIONAHA.108.120212. Epub 2008 Nov 10.

Angiotensin II-dependent hypertension increases Na transport-related oxygen consumption by the thick ascending limb

Guillermo B Silva  1 , Jeffrey L Garvin
Affiliations

Angiotensin II-dependent hypertension increases Na transport-related oxygen consumption by the thick ascending limb

Guillermo B Silva et al. Hypertension. 2008 Dec.

Abstract

Renal medullary superoxide (O(2)(-)) increases in angiotensin (Ang) II-dependent hypertension. O(2)(-) increases thick ascending limb Na transport, but the effect of Ang II-dependent hypertension on the thick ascending limb is unknown. We hypothesized that Ang II-dependent hypertension increases thick ascending limb NaCl transport because of enhanced O(2)(-) production and increased protein kinase C (PKC) alpha activity. We measured the effect of Ang II-dependent hypertension on furosemide-sensitive oxygen consumption (a measure of Na transport), O(2)(-) production, and PKCalpha translocation (a measure of PKCalpha activity) in thick ascending limb suspensions. Ang II-dependent hypertension increased furosemide-sensitive oxygen consumption (26.2+/-1.0% versus 36.6+/-1.2% of total oxygen consumption; P<0.01). O(2)(-) was also increased (1.1+/-0.2 versus 3.2+/-0.5 nmol of O(2)(-)/min per milligram of protein; P<0.03) in thick ascending limbs. Unilateral renal infusion of Tempol decreased O(2)(-) (2.4+/-0.4 versus 1.2+/-0.2 nmol of O(2)(-)/min per milligram of protein; P<0.04) and furosemide-sensitive oxygen consumption (32.8+/-1.3% versus 24.0+/-2.1% of total oxygen consumption; P<0.01) in hypertensive rats. Tempol did not affect O(2)(-) or furosemide-sensitive oxygen consumption in normotensive controls and did not alter systolic blood pressure. Ang II-dependent hypertension increased PKCalpha translocation (5.7+/-0.3 versus 13.8+/-1.4 AU per milligram of protein; P<0.01). Unilateral renal infusion of Tempol reduced PKCalpha translocation (5.0+/-0.9 versus 10.4+/-2.6 AU per milligram of protein; P<0.04) in hypertensive rats. Unilateral renal infusion of the PKCalpha inhibitor Gö6976 reduced furosemide-sensitive oxygen consumption (37.4+/-1.5% versus 25.1+/-1.0% of total oxygen consumption; P<0.01) in hypertensive rats. We conclude that Ang II-dependent hypertension enhances thick ascending limb Na transport-related oxygen consumption by increasing O(2)(-) and PKCalpha activity.

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Figures

Figure 1
Figure 1
A, Longitudinal section of the infused kidney. B, Area stained by the infusion of Coomassie blue R250. Intense traces of dye were found in the catheter’s pathway corticomedullary boundary and outer medulla. To much less extent, the dye was found in the inner medullary region. Stippled area depicts the area of tissue used to perform the experiments.
Figure 2
Figure 2
Effect of Ang II–dependent hypertension on thick ascending limb transport–related oxygen consumption (n=6). Transport-related oxygen consumption was measured as furosemide-sensitive oxygen consumption.
Figure 3
Figure 3
Effect of Ang II–dependent hypertension on O2− production in the thick ascending limb (n=8).
Figure 4
Figure 4
Effect of renal unilateral infusion of Tempol on thick ascending limb (TAL) transport-related oxygen consumption during Ang II–dependent hypertension (n=8). Transport-related oxygen consumption was measured as furosemide-sensitive oxygen consumption.
Figure 5
Figure 5
Effect of renal unilateral infusion of Tempol on thick ascending limb (TAL) O2− production in Ang II–dependent hypertension (n=7).
Figure 6
Figure 6
Effect of Ang II–dependent hypertension on thick ascending limb PKCα translocation (n=6). Equal amounts of protein were loaded from normotensive and hypertensive cytosolic (8 µg) and particulate (20 µg) fractions.
Figure 7
Figure 7
Effect of renal unilateral infusion of Tempol on PKCα translocation in the thick ascending limb (TAL) in Ang II–dependent hypertension (n=7). Equal amounts of protein were loaded from Tempol-treated and nontreated cytosolic (8 µg) and particulate (20 µg) fractions.
Figure 8
Figure 8
Effect of renal unilateral infusion of Gö6976 on thick ascending limb (TAL) transport-related oxygen consumption during Ang II–dependent hypertension (n=6). Transport-related oxygen consumption was measured as furosemide-sensitive oxygen consumption.
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