Association of mitochondrial SOD deficiency with salt-sensitive hypertension and accelerated renal senescence

Abstract

Mitochondria are the major source of superoxide (O(2)(-)) in the aerobic organisms. O(2)(-) produced by the mitochondria is converted to hydrogen peroxide by mitochondrial superoxide dismutase (SOD2). Mice with complete SOD2 deficiency (SOD2(-/-)) exhibit dilated cardiomyopathy and fatty liver leading to neonatal mortality, whereas mice with partial SOD2 deficiency (SOD2(+/-)) show evidence of O(2)(-)-induced mitochondrial damage resembling cell senescence. Since earlier studies have provided compelling evidence for the role of oxidative stress and tubulointerstitial inflammation in the pathogenesis of hypertension, we tested the hypothesis that partial SOD2 deficiency may result in hypertension. Wild-type (SOD2(+/+)) and partial SOD2-deficient (SOD2(+/-)) mice had similar blood pressures at 6-7 mo of age, but at 2 yr SOD2(+/-) mice had higher blood pressure. Oxidative stress, renal interstitial T-cell and macrophage infiltration, tubular damage, and glomerular sclerosis were all significantly increased in 2-yr-old SOD2(+/-) mice. High-salt diet induced hypertension in 6-mo-old SOD2-deficient mice but not in wild-type mice. In conclusion, partial SOD2 deficiency results in oxidative stress and renal interstitial inflammation, changes compatible with accelerated renal senescence and salt-sensitive hypertension. These findings are consistent with the pattern described in numerous other models of salt-sensitive hypertension and resemble that commonly seen in elderly humans.

Salt-sensitive hypertension in mitochondrial superoxide dismutase deficiency is associated with intra-renal oxidative stress and inflammation

“…In confirmation of our earlier study [3], consumption of the high salt diet resulted in a significant increase in arterial pressure in the MnSOD-deficient mice but not in the wildtype mice. This phenomenon illustrates the association of MnSOD deficiency with salt-sensitivity.…”

“…This was associated with renal interstitial accumulation of lymphocytes and macrophages (Fig. 5) as shown in our earlier study [3] pointing to the susceptibility of the MnSOD-deficient mice to high salt diet-induced renal inflammation.…”

“…In fact, as shown in our original study, development of hypertension in MnSOD-deficient mice fed a high salt diet was associated with significant renal interstitial infiltration of T lymphocytes and macrophages [3]. Hypertension in the MnSODdeficient mice consuming a high salt diet was associated with a marked increase in phosphorylated IjB.…”

“…However, heterozygous mice with partial MnSOD deficiency (MnSOD ?/-) survive but show evidence of superoxide-induced mitochondrial damage and senescence [2]. Earlier studies have shown that a high salt diet causes hypertension in MnSOD-deficient (MnSOD ?/-) mice but not in wild-type mice [3]. Oxidative stress and renal interstitial inflammation are invariably present and play a major role in elevation of arterial pressure in animal models of genetic and acquired hypertension.…”

Reactive oxygen species and vascular biology: implications in human hypertension

“…54 Impaired activity and/or decreased expression of mitochondrial electron transport chain complexes I, III and IV have been implicated in vascular aging and cardiovascular disease, 55 and an association between mitochondrial dysfunction and blood pressure has been reported in human and experimental hypertension. [56][57][58] Ang II-sensitive hypertension is also linked to mitochondrial-derived oxidative stress, as AT 1 receptor blockade attenuates H 2 O 2 production 59 and mitochondrial dysfunction in SHR, and in mice, Ang II infusion is associated with decreased expression of cardiac mitochondrial electron transport genes. 60 In deoxycorticosterone acetate-salt hypertension, mitochondrial-derived ROS, via endothelin-1/endothelin A receptors, has an important role in oxidative vascular damage.…”