12 ―― 亜鉛栄養治療

Editorial

6巻1号

Zinc and oxidative stress ―― 132015

Role of Zn in blood pressure
and renal function

describe the novel aspects, the deterioration ofIntroduction

blood pressure (BP) and renal function observed

Zinc (Zn), is an essential trace element inin Zn-deficient and Zn-excess rats.

1-3)

humans and animals . Zn deficiency causes avariety of physical disorders derived from the1．Role of Zn-excess ingestion inblood pressure and renal function

skin epithelium, the gastrointestinal system, theDepartment of Public Health and Environmental Medicine, Faculty of Medicine, The Jikei University School of Medicine

Hiroyuki Yanagisawa
Abstract

reproductive system, the neural system, theRats fed on 22 g/day of 0.05% Zn-excess diet (11endocrine system, the ocular system and the1-3). Zn tablets and Zn-mgZn/day) and 0.2% Zn-excess diet (44 mgZn/supplemented food have been recently circulatingday) for 4 weeks showed a dose-dependent

in Japan, the USA and Europe in order to obtain

increase in basal systolic blood pressure (BP),immune system

good health and health promotion . Moreover,diastolic BP and mean BP levels3,6,7) and a dose-inulin clearance. The fall in inulin clearance may be the result of a decline in RBF.

oral Zn therapy has been more recently done todependent decrease in basal renal blood flow

Intravenous injection of the nitric oxide (NO) synthase inhibitor, L-NAME potentiated antreat hypogeusia and decubitus ulcers in adults

2,3)(RBF) and inulin clearance levels3,7) relative to rats

increase in BP and a decrease in RBF in the Zn-excess setting. However, intravenousand hypogonadism and growth retardation fromfed on a control diet containing 0.005% Zn (1.1Zn-excess ingestion elevated blood pressure (BP) and reduced renal blood flow (RBF) and2,3)

administration of the exogenous superoxide radical scavenger, tempol significantly reduced

infants to adolescents . However, Zn toxicity hasmgZn/day) for 4 weeks (Fig.1). These findings

BP and substantially augmented RBF in the Zn-excess setting. Resultantly, tempol treatment

not been fully understood. Here, we therefore

indicate an increase in basal systemic BP levels

restored BP and RBF levels observed in the Zn-excess setting to levels comparable to those4,5)

seen in the control setting. These findings suggest that both an increment in BP and adecrement in RBF observed in the Zn-excess setting result from a decrement in the actionof the vasodilator, NO through peroxynitrite formation derived from the non-enzymatic
reaction of NO with increased superoxide radical. In fact, the activity of the endogenous
superoxide radical scavenger, Cu/Zn-superoxide dismutase (SOD) was significantly
diminished in the vessel wall of the Zn-excess vs. the control setting. The reduction in theAactivity of Cu/Zn-SOD in the Zn-excess setting was the effect of Cu deficiency secondary
to Zn-excess ingestion. With regard to BP, RBF, inulin clearance, L-NAME and tempol
treatment and the activity of Cu/Zn-SOD, similar results were seen in the Zn-deficientsetting. Therefore, inadequate intake of Zn causes the aggravation of BP and renal function
via superoxide radical-induced oxidative stress.
KEY WORDS

Zinc, Blood pressure, Renal function, Oxidative stress,		

Cu/Zn-superoxide dismutase

Correspondence to：Hiroyuki Yanagisawa, M.D., Ph.D.

B

Department of Public Health and Environmental Medicine, Faculty of Medicine, The Jikei
University School of Medicine, 3-25-8 Nishishimbashi, Minato-ku, Tokyo 105-8461, Japan
TEL：81-3-3433-1111 Ext. 2270
FAX：81-3-3431-6029
E-mail：hryanagisawa@jikei.ac.jp

Fig.1
Basal blood pressure (mmHg) levels (A) and basal renal blood flow (arbitrary units) and inulin clearance (ml/min/g kidney weight)
levels (B) obtained from rats fed on a control diet containing 0.005% Zn or two Zn-excess diets containing 0.05% Zn or 0.2% Zn for 4weeks. Blood pressure, renal blood flow and inulin clearance were measured at 4 weeks after the start of dietary treatment. Datareported represent means ± SD of the values obtained from seven rats in each group. Statistical analysis was based upon one-way
analysis of variance. References3,7)

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Zinc and oxidative stress ―― 152015

and a fall in basal renal function derived from Zn3,7)

a decrease in mean BP levels3,7,8) and an elevation
7,8)

excess intake . The fall in inulin clearance in ratsin RBF levels

fed on two Zn-excess diets may be due to atwo Zn-excess diets (Fig.3). These observations
indicate that superoxide radical may be a modifier

staining exhibited no significant morphologicof systemic BP and renal function through achanges in the kidneys from rats fed a 0.2% Zn-reduction in the action of the vasodilator, NO

excess diet .

Bin rats fed on a control diet anddecrease in RBF because hematoxylin-eosin (H-E)

3,7)

A

based on the formation of peroxynitrite in rats

Intravenous administration of the NOS
ωfed on two Zn-excess diets3,7,8) (Fig.4). Thus, theinhibitor, N -nitro-L-arginine methyl ester

mechanisms underlying an elevation in systemic(L-NAME) elevated mean BP levels 3,7,8) andBP and the deterioration of renal function in rats7,8)

in rats fed on a control dietfed on two Zn-excess diets may be due to an

and two Zn-excess diets (Fig.2). The mean BP

increase in the action of superoxide radical in thereduced RBF levels

reducedvessel wall 3,7,8) . Actually, a dose-dependent

were comparable among the three groups of rats.

increment in 8-hydroxy-2’-deoxyguanosine

These observations suggest the involvement offormation caused by enhanced superoxide radical

NO in the regulation of systemic BP and RBF in

production was observed in rats fed on two Zn-3,7,8). Thus, the vasodilator,

excess diets relative to rats fed on a control

NO may play a central role in suppressing andiet3,7). Additionally, the activity of the intrinsic

elevation in systemic BP and a fall in renal

superoxide radical scavenger, Cu/Zn-SOD in thefunction in the Zn-excess setting3,7,8).

thoracic aorta was significantly reduced in rats

levels elevated6-8)

and the RBF levels

the three groups of rats3,7)Intravenous injection of the membrane-fed on two Zn-excess diets relative to rats fed on

permeable SOD mimetic compound, 4-hydroxy-a control diet in a dose-dependent manner3,7,8).

2,2,6,6-tetramethylpiperidine-1-oxyl (tempol) caused

This fall in the activity of Cu/Zn-SOD may be theAB

Fig.3
Effects of tempol treatment on mean blood pressure (mmHg) levels (A) and renal blood flow (arbitrary units) levels (B) seen in rats
fed a control diet containing 0.005% Zn or two Zn-excess diets containing 0.05% Zn or 0.2% Zn for 4 weeks. Data reported
represent means ± SD of the values obtained from eight rats in each group. Statistical analysis was based upon two-way analysisof variance. White bars; basal condition groups. Black bars; tempol treatment groups. Reference3,7)

Fig.4
Peroxynitrite formation as a result of non-enzymatic reaction of nitric oxide with superoxide radical. Reference3)

result of Cu deficiency secondary to Zn-excess

found a significant and dose-dependent increase iningestion, contributing to an increment in thethe potent vasoconstrictor, angiotensin Ⅱ in theaction of superoxide radical in the vessel wall ofkidneys of rats fed on two Zn-excess diets relative3,7,8)

rats fed on two Zn-excess diets.

to those of rats fed on a control diet 3,8). This

There were no significant differences in mean

increased angiotensin Ⅱ may contribute in part toBP and RBF levels after L-NAME or tempol

an alteration in RBF levels seen in Zn-excess

treatment among rats fed on a control diet andintake3,8).

two Zn-excess diets3,7,8) (Figs.3, 4). Mean BP levelsobtained from rats fed on two Zn-excess diets
were essentially comparable to those obtained
from rats fed a control diet3,7,8). However, RBF

Fig.2
Effects of L-NAME treatment on mean blood pressure (mmHg) levels (A) and renal blood flow (arbitrary units) levels (B) seen inrats fed a control diet containing 0.005% Zn or two Zn-excess diets containing 0.05% Zn or 0.2% Zn for 4 weeks. Data reported
represent means ± SD of the values obtained from seven rats in each group. Statistical analysis was based upon two-way analysis
of variance. White bars; basal condition groups. Black bars; L-NAME treatment groups. Reference3,7)2．Effects of zinc-deficient intake onblood pressure and renal functionlevels obtained from rats fed on two Zn-excess

Spontaneously hypertensive rats (SHR) fed ondiets were somewhat different from thosea Zn-deficient diet for 4 weeks exhibited aobtained from rats fed on a control diet3,7). Thissignificant elevation in systolic BP levels at 2

observation suggests that in addition to both NO

and 4 weeks following the initiation of dietaryand superoxide radical, some vasoconstrictive

treatment relative to SHR fed on a control dietfactor takes part in the modulation of RBF levelsfor 4 weeks3,9). Intravenous L-NAME treatment3,7)in the Zn-excess settings . We have recently

significantly increased mean BP levels in SHR

16 ―― 亜鉛栄養治療

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Zinc and oxidative stress ―― 172015

fed on a control or a Zn-deficient diet for 4weeks3,9). Mean BP levels after L-NAME

deficient diet for 4weeks than in rats fed on aweeks may be due to a fall in the action of thescavenger, Cu/Zn-SOD was significantly reduced3,9)vasodilator, NO based upon an elevation in thein the kidneys of rats fed a Zn-deficient diet forcontrol diet for 4 weeks .

administration were comparable in the two3,9)Normotenvive rats (NMR) fed on a Zn-groups of rats , demonstrating the involvement

deficient diet for 4 weeks had no significantof the vasodilator, NO in the regulation of BP.

increases in mean BP levels during the dietary

Inversely, intravenous tempol administration

manipulation relative to NMR fed on a normal
3,10,11). However, NMR fed on asignificantly decreased mean BP levels in SHR

diet for 4 weeks

fed on a control or a Zn-deficient diet for 4

Zn-deficient vs. a normal diet for 4 weeks

3,9)

action of superoxide radical

3,11). Indeed, theactivity of the intrinsic superoxide radical

3．Summary and conclusions

4 weeks relative to rats fed a control diet for 4
weeks3,11).
adequate intake of Zn is essential to maintain BP
and renal function (Fig.5).

Zn contributes to the regulation of BP andAs shown in Fig.1, values for both systemic BPweeks . As a consequence, intravenous tempol

showed a significant reduction in RBF levels andrenal function. Both the Zn-deficient and Zn-and RBF seen in rats fed a 0.05% Zn-excess dietadministration completely restored mean BPa significant elevation in renal vascularexcess settings alter BP levels and renal function(11 mgZn/day) were at the borderline in statisticallevels observed in SHR fed on a Zn-deficient dietresistance (RVR) levels, resulting in a fall in

via superoxide radical-induced oxidative stress.

significance relative to those obtained from rats. Intravenous L-NAME

The mechanisms may be a reduction in the action

fed a control diet (1.1 mgZn/day). This suggests,

treatment significantly augmented mean BP andof the vasodilator, NO derived from the formationthat the lowest observed adverse effect level ofindicating the participation of superoxide radical

RVR levels and significantly reduced RBF levelsof peroxynitrite generated by the non-enzymatic

Zn is approximately 11 mg/day in rats3,7).

in the regulation of BP. Similar to the Zn-excess

in rats fed on a control or a Zn-deficient diet forreaction of NO with superoxide radical. Thus,for 4 weeks to levels comparable to those seenin SHR fed on a control diet for 4 weeks

setting for 4 weeks

3,6-8)

3,9), these findings

inulin clearance

4 weeks

3,10,11)

3,10,11). However, intravenous tempol

demonstrate that an increase in BP levels

administration significantly decreased mean BP

observed in SHR fed on a Zn-deficient diet for 4and RVR levels in rats fed on a control or a Zn-weeks may be the result of a decrease in thedeficient diet for 4 weeks, while there are no１）Vallee BL, Falchuk KH：The biochemicalcauses the deterioration of renal function

action of the vasodilator, NO based upon thesignificant differences in RBF levels between thebasis of zinc physiology. Physiol Rev 73：79-

accompanied by an elevation in systemic bloodformation of peroxynitrite derived from the non-two groups of rats3,11). These observations are118, 1993

pressure primarily through superoxide-induced

enzymatic reaction of NO with increased levels

similar to those observed in the Zn-excess

3,9)

3,6-8)

of superoxide radical . In fact, the activity ofsetting. Therefore, the mechanisms

Cu/Zn-SOD scavenging superoxide radical wasunderlying the aggravation of renal function

significantly diminished in rats fed on a Zn-observed in rats fed a Zn-deficient diet for 4◆ References ―――――――

２）Yanagisawa H：Zinc deficiency and clinicaloxidative stress. Int J Toxicol 33：288-296, 2014

practice - validity of zinc preparations-.

８）Kasai M, Yanagisawa H, et al：Excessive zinc

Yakugaku Zasshi 128：333-339, 2008３）Yanagisawa H, et al：Inadequate intake ofreduces renal blood flow via kidney angiotensin

zinc exacerbates blood pressure and renal

II in rats. Biol Trace Elem Res 150：285-290,

function via superoxide radical-induced

2012oxidative stress. Biomed Res Trace Elements
26：117-123, 2015

aggravates hypertension in spontaneously
hypertensive rats：possible role of Cu/Zn-supplements for children. Am J Clin Nutr 68：

superoxide dismutase. Clin Exp Hypertens 24：

495S-498S, 1998

355-370, 2002５）B lack MM：Zinc def iciency and child10）Sato M, Yanagisawa H, et al：Dietary Zn

development. Am J Clin Nutr 68：464S-498S,

deficiency does not influence systemic blood

1998
elevates systemic blood pressure levels inFig.5９）Sato M, Yanagisawa H, et al：Zn deficiency４）A l l e n L H ： Z i n c a n d m i c r o n u t r i e n t６）Yanagisawa H, et al：Excessive zinc intake

U-shaped relationship between Zn ingestion and function. Reference3)

intake increases systemic blood pressure andpressure and vascular nitric oxide signaling in
normotenvive rats. Biol Trace Elem Res 91：
157-171, 2002

normotensive rats-potential role of superoxide-11）Kurihara N, Yanagisawa H, et al：Increased

induced oxidative stress-. J Hypertens 22：543-

renal vascular resistance in zinc-deficient rats:550, 2004.
７）Y anagisawa H, et al：Zinc-excess intakerole of nitric oxide and superoxide. Clin Exp
Pharmacol Physiol 29：1096-1104, 2002