title: Upregulation of renal eNOS by high-sodium diet facilitates hypertension in doxorubicin-treated rats through enhanced oxidative stress.
abstract: 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.
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Hirai
authors.forename: Kenji
authors.initials: K
authors.lastname: Okumura
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nishimoto
authors.forename: Takanori
authors.initials: T
authors.lastname: Shumiya
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Murakami
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Takahashi
authors.forename: Toru
authors.initials: T
authors.lastname: Asai
authors.forename: Hisashi
authors.initials: H
authors.lastname: Murakami
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Numaguchi
authors.forename: Hideo
authors.initials: H
authors.lastname: Matsui
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
mesh_terms: 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
chemical_list: D000903:Antibiotics, Antineoplastic; D012982:Sodium, Dietary; D004317:Doxorubicin; D000080242:8-Hydroxy-2'-Deoxyguanosine; D052250:Nitric Oxide Synthase Type III; D003849:Deoxyguanosine