Detailed Strain Information

系統

系統:	DSS, SS, S/Jｒ, Dahl S (Dahl salt-sensitive rat )
キーワード:	食塩感受性高血圧
由来:	米国 Brookhaven National Laboratories の Dahlによりoutbred の Sprague-Dawley 系ラットコロニーから高食塩食による高血圧発症を指標とした選抜・交配により1962年に確立された系統であり、Dahl Salt-Sensitive Ratと称された。同時に高食塩食によっても高血圧を発症しない（抵抗性の）系統も作出された。これはDahl Salt-Resistant Rat と称され、Dahl Salt-Sensitive Rat の正常対照として利用されている。その後 J. Rappにより近交化され、SS/JrラットとSR/Jrラットが、またNIHで Iwai と Hansen により近交化され、DSS/Nと称される系統が確立された。これは Dahl-Iwai-Salt-sensitive ラットとも称される。SS ラットとSR ラットは同じコロニー由来ではあるが、outbred を起源とするためお互いに遺伝的隔たりを持つ。DNAフィンガープリント法で調べるとSS ラットとSR ラットは80%のバンドを共通に持つとされる。これらのことよりSRラットをSSラットのコントロールとすることは妥当であるとされている。1984 年の本ラットに関する総説中ではSSラットはRappによりS/JRとも称され、また同じ系統が Mollegard （Copenhagen）によりDahl Sと称されるようになった。　日本へは1987 年にデンマークの Mollegard 社から（株）成和実験動物研究所 (SEA) に、また1989 年に Iwai からエーザイに分与されている。これらの系統は明らかに遺伝的に分化しているので、使用および実験結果の解釈には注意を要する。
表現型・病態:	原報では Dahl Salt-Sensitive Rat は8％食塩食により3-4 週後に fulminant 高血圧と著明な血管および腎障害を発症し、8 週以内に100％死亡する。0.3％食塩食でも徐々に血圧は上昇し顕著な高血圧症を呈するが、死亡することはないとされている。成和実験動物研究所の Dahl S ラットでは４％食塩食を与え続けた5 週後に血圧は約 200mmHg に上昇する。8 週後には雄で 220～230mmHg に、雌で 210～220mmHg に達する。Dahl Salt-Resistant Ratでは雌雄ともに120～140mmHgである。高血圧は52%の高ショ糖食によっても誘導される。DahlR 系ラットにDahlS 系ラットの腎臓を移植することにより、DahlR 系ラットを食塩感受性に転換することが可能である。また、DahlR 系ラットの循環器系にDahlS 系ラットの循環器系を連結する交叉還流術によっても DahlR 系ラットを食塩感受性に転換することが可能である。　DahlS 系ラットは DahlR 系ラットに比べ腎糸球体の数が15％減少している。腎障害はアルブミンやイムノグロブリン等の高分子蛋白の尿中への排泄の亢進として現れる。　高率に白内障を発症する。　1 産目は約8匹の仔を産むが、2 産目以降は高血圧のため産仔数が減少する。
病因（原因遺伝子）:	交叉還流術によりDahlR 系ラットを食塩感受性に転換することが可能であることより、血液中の何らかの因子の関与が推察される。これまでに様々な物質の関与が報告されている。　hyporesponsive kidneys と心房からの atrial natriuretic factor の遊離の減少を含むatrial natriuretic factor（心房性利尿ペプチド）に欠陥のあることが報告されている。　高食塩食を負荷されたDahlS 系ラットは神経刺激および norepinephrine に対して高感受性である。これは hyperernoradrenergic innervation 、または elevated neuropeptide Y innervation 、あるいは altered release of transmitter により説明可能かもしれない。Naloxone は高血圧を少し減弱させるが、これは摂餌量、すなわち摂取する塩量の減少の2 次的な効果かもしれない。DahlS 系ラットとSHR系ラットの F1 交雑仔で、かつ雌のSHR により養育された個体は雌のDahlS に養育された F1 交雑仔に比べ35日齢では体重が軽く、高食塩食を負荷されると急速に高血圧を発症する。母系の環境効果が高血圧の発症に重要な影響をもつことがで DahlS, SHR と WKY を用いた交配実験により示唆されている。　afferent arterioles and interlobular arteriesのmyogenic responsivenessの減少がimpared renal autoregulation の原因と報告されている。　高血圧の原因遺伝子として最も可能性の高いものは第7染色体上の11 β-hydroxylase 遺伝子である。DahlR 系ラットでは11 β-hydroxylase 蛋白に5個のアミノ酸置換がある。これはDahlS系ラットを含む他の12系統のラットにはみられない。DahlR 系ラットではミネラルコルチコイドである18-OH-DOCの合成能が低下しており、これが DahlR 系ラットの食塩食抵抗性の一因であることが示唆される。　DahlS ラットと他系統ラットとの F2 ラットを用いた遺伝的連鎖解析により、11 β-hydroxylase 遺伝子の他にも以下のようないくつかの染色体領域に高血圧に関連すると考えられる遺伝子と高血圧との遺伝的連鎖が報告されている。第3染色体上の endothelin-3 は血圧と心臓重量に遺伝的相関を示す。　高血圧は angiotensin のレベルに一部起因するが、これは renin が正常にフィードバックされない条件下に限られる。　dopamine-DA(1) receptor の欠陥も報告されている。　食塩の排泄障害に起因するという説もある。
臨床への応用、有用性:	ヒトの食塩感受性高血圧、心不全のモデルとして有用性が高い。　抗高血圧薬 cicletanine の投与により血圧は下降し、さらに腎臓の機能および形態的傷害は改善される。これは腎ホモジネート中の脂質の過酸化の減弱と相関しており、このことよりcicletanine が antioxidant として働き高血圧を防止していることを示している。高血圧は同じく antioxidant であるIndapamide によっても防止される。L-argenine の長期投与により高血圧は予防され、pressure-natriuretic responseも正常化される。この効果は腎障害の防止によるものではなく、食塩感受性系統に特異的なものである。これは一部は腎糸球体での濾過率の自律的調節の改善によるものかもしれない。
維持機関:	(株）エーザイセアック吉富株式会社 (2001年5月25日現在)
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執筆者記録:	森　政之（信州大学）2001年5月25日, TS:4/21/03
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