Upregulation of renal eNOS by high-sodium diet facilitates hypertension in doxorubicin-treated rats through enhanced oxidative stress.
It is known that renal nitric oxide (NO) is an important controller of urinary sodium excretion. A defect in the kidney's NO system could cause salt-sensitive hypertension. Since it has been demonstrated that doxorubicin binds to the reductase domain of endothelial NO synthase (eNOS) and generates superoxide in vitro, we tested our hypothesis that a high-sodium diet would upregulate the expression of eNOS and enhance oxidative stress in the kidney of doxorubicin-treated rats, resulting in a facilitation of hypertension. At 4 weeks after treatment with doxorubicin in Sprague-Dawley rats, the systolic blood pressure significantly increased only in the high-sodium diet group. The expressions of eNOS protein in the renal cortex and medulla were significantly higher in high-sodium groups than in normal-sodium groups, regardless of doxorubicin treatment. In rats treated with doxorubicin, a biomarker of oxidative damage 8-hydroxy-2'-deoxyguanosine (8-OHdG) immunohistological staining of renal tissues showed strong staining of the proximal and distal tubules. In particular, rats with doxorubicin in the high-sodium diet group demonstrated a significant increase in urinary exertion of 8-OHdG as well as more prominently stained tubules against 8-OHdG antibody, but markedly lower urinary NO(x) excretion than in rats without doxorubicin, even than in the untreated, low-sodium group. In conclusion, these results indicate that the oxidative stress induced by doxorubicin impairs NO production in the kidney. As such, doxorubicin treatment appears to contribute to the development of salt-sensitive hypertension through reductive activation of upregulated eNOS by a high-sodium diet instead of NO production.
Hirai
Toshihisa
T
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
Okumura
Kenji
K
Nishimoto
Yasuhiro
Y
Shumiya
Takanori
T
Murakami
Ryuichiro
R
Takahashi
Ryotaro
R
Asai
Toru
T
Murakami
Hisashi
H
Numaguchi
Yasushi
Y
Matsui
Hideo
H
Murohara
Toyoaki
T
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D001794:Blood Pressure / Q000187:drug effects; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004317:Doxorubicin / Q000633:toxicity*; D018565:Food-Drug Interactions; D006973:Hypertension / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D007124:Immunoenzyme Techniques; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D012982:Sodium, Dietary / Q000008:administration & dosage*; D015854:Up-Regulation
D000903:Antibiotics, Antineoplastic; D012982:Sodium, Dietary; D004317:Doxorubicin; D000080242:8-Hydroxy-2'-Deoxyguanosine; D052250:Nitric Oxide Synthase Type III; D003849:Deoxyguanosine