SOD1 Limits Renal Microvascular Remodeling and Attenuates Arteriole and Blood Pressure Responses to Angiotensin II via Modulation of Nitric Oxide Bioavailability

摘要

Oxidative stress is associated with vascular remodeling and increased preglomerular resistance that are both implicated in the pathogenesis of renal and cardiovascular disease. Angiotensin II induces superoxide production which is metabolized by superoxide dismutase (SOD) or scavenged by nitric oxide.We investigated the hypothesis that SOD1 regulates renal microvascular remodeling, blood pressure and arteriolar responsiveness and sensitivity to angiotensin II, using SOD1-transgenic (SOD1-tg) and SOD1-knockout (SOD1-ko) mice.Blood pressure, measured telemetrically, rose more abruptly during prolonged angiotensin II infusion in SOD1-ko mice. The afferent arteriole media-to-lumen ratios were reduced in SOD1-tg and increased in SOD1-ko mice. Afferent arterioles from non-treated wild-types had graded contraction to angiotensin II (sensitivity: 10^-9 mol/l, responsiveness: 40%). Angiotensin II contraction were less sensitive (10^-8 mol/l) and responsive (14%) in SOD1-tg, but more sensitive (10^-13 mol/l) and responsive (89%) in SOD1-ko mice. Arterioles from SOD1-ko had 4-fold increased superoxide formation with angiotensin II at 10^-9 mol/l. L-NAME reduced arteriole diameter of SOD1-tg, and enhanced angiotensin II sensitivity and responsiveness of wild-type and SOD1-tg to the level of SOD1-ko mice. Tempol increased arteriole diameter and normalized the enhanced sensitivity and responsiveness to angiotensin II of SOD1-ko, but did not affect wild-type or SOD1-tg mice. Neither SOD1-deficiency nor overexpression was associated with changes in nitrateitrite excretion, or renal mRNA expression of NOS-, NADPH oxidase-, SOD2/SOD3-isoforms, and angiotensin II receptors.In conclusion, SOD1 limits afferent arteriole remodeling and reduces sensitivity and responsiveness to angiotensin II by reducing superoxide and maintaining nitric oxide bioavailability. This may prevent an early and exaggerated blood pressure response to angiotensin II.