Up-regulation of kidney NAD(P)H oxidase and calcineurin in SHR: Reversal by lifelong antioxidant supplementation

doi:doi:10.1111/j.1523-1755.2004.00372.x

Abstract

Up-regulation of kidney NAD(P)H oxidase and calcineurin in SHR: Reversal by lifelong antioxidant supplementation.

Background

Spontaneously hypertensive rats (SHR) are born normotensive and develop hypertension (HTN) later in life (age 4 to 5 weeks). HTN in SHR is associated with and caused in part, by oxidative stress and renal interstitial inflammation. This study tested the hypothesis that lifelong antioxidant supplementation beginning at prenatal period may delay the onset and reduce the severity of HTN in SHR. The study further sought to explore the effect of diet modification on renal tissue NAD(P)H oxidase and calcineurin abundance.

Methods

Pregnant SHR and their offspring were fed either an antioxidant-fortified diet (a chow containing alpha -tocopherol 5000 IU/kg, ascorbic acid 500 ppm, selenium 2.76 ppm, and zinc 350 ppm) or regular diet ( alpha -tocopherol 40 IU/kg, selenium 0.2 ppm, and zinc 70 ppm). Animals were observed for 24 weeks. Wistar-Kyoto rats fed either a regular or antioxidant diet served as control.

Results

Onset of HTN was delayed and severity of HTN was reduced in antioxidant-treated compared with untreated SHR. Markers of oxidative stress (i.e., plasma hydrogen peroxide, renal tissue malondialdehyde, and nitrotyrosine abundance) were elevated in untreated but not in antioxidant-treated SHR. gp91^phox and p22^phox subunits of NAD(P)H oxidase were markedly elevated in the renal cortex of untreated SHR and partially restored in the treated SHR. Similarly, renal calcineurin A alpha and B subunits were elevated in untreated SHR and were partially restored in the treated SHR. Antioxidant therapy had no effect on the measured parameters in the WKY control.

Conclusion

Lifelong consumption of antioxidant-rich diet ameliorates HTN and oxidative stress in SHR. This is associated with the reduction of superoxide-generating enzyme, NAD(P)H oxidase, and immunoregulatory factor calcineurin. Antioxidant-rich diet appears to attenuate oxidative stress, not only by fortifying antioxidant defense capacity but also by lowering NAD(P)H oxidase, which is a major source of reactive oxygen species.

Keywords:

oxidative stress, hypertension, NAD(P)H oxidase, calcineurin, kidney

Vascular Biology – Hemodynamics – Hypertension