੕ହ৬৔ৎੑभী৕ਃଡ॑੦ೕधखञཿਙႲට୰भৎ৑୰ଙ‫؞‬ৎ৑൉ఇଢ଼஢পૺ ൄ൞叞‫ ెૈ؜‬ઉ࿙ృପপ৾ প৾੹ఇ৾ଢ଼஢੹ ఇද৾ী৙➹⪅ࡣࡇࢀࡲ࡛࡟ࠊྠࡌ⸆࡛ࡶ᭹⸆᫬้࡟ࡼࡾຠᯝࡸ๪స⏝ࡀ␗࡞ࡿ࡜࠸ࡗࡓ་⸆ရࡢ㐺ṇ౑⏝㸦᫬㛫⫱⸆㸧࡟ຍ࠼࡚ࠊᴫ᪥ࣜࢬ࣒࡟╔┠ࡋࡓ᫬㛫๰⸆ࢆᐇ㊶ࡋ࡚ࡁࡓࠋࡑࡢ◊✲ࡢ≉ᚩࡣࠊ๰⸆࣭་⸆ရࡢ㐺ṇ౑⏝࡟㛵ࡍࡿᶆⓗࢆศᏊ࣭⣽⬊࣭⮚ჾ㐃㛵ࡢࣜࢬ࣒ࡢどⅬ࠿ࡽ᥈⣴ࡋࠊࡇࢀࡲ࡛ὀ┠ࡉࢀ࡚࠸࡞࠿ࡗࡓࢩ࣮ࢬࢆⓎぢࡋࠊഅ↛ᛶ࡟㢗ࡽ࡞࠸ྜ⌮ⓗ࡞᪉ἲㄽࢆලయ໬ࡋࡓⅬ࡟࠶ࡿࠋ௒᪥࡛ࡣࠊࡇࢀࡽඛ㐍ⓗ࡞ᐇ⦼࡜◊✲ࣜࢯ࣮ࢫࢆ᭱኱㝈࡟ά⏝ࡋࡓ⊂๰ⓗ࡞◊✲ᡂᯝࡀࠕ᫬㛫⫱⸆࣭᫬㛫๰⸆ࠖࡢᴫᛕࡢᥦၐ࡟ࡘ࡞ࡀࡗ࡚࠸ࡿࠋ៏ᛶ⭈⮚⑓㸦chronic kidney disease; CKD㸧ࡣࠊ⭈ᶵ⬟ࡢపୗࡀ៏ᛶⓗ࡟⥆ࡃ⑓ែࡢ⥲⛠࡛࠶ࡾࠊᮏ㑥࡛ࡢ⨯ᝈᩘࡣᡂேேཱྀࡢ⣙ 13%࡜᥎ィࡉࢀ࡚࠸ࡿࡇ࡜࠿ࡽࠊ῝้࡞♫఍ၥ㢟࡜ࡉࢀ࡚࠸ࡿࠋ⌧ᅾࡢ
CKD ἞⒪ࡣᑐ⑕⒪ἲࡀᇶᮏ࡛࠶ࡾࠊ⭈ᶵ⬟ࢆಖㆤࡲࡓࡣᨵၿࡍࡿ἞⒪ࡣ⭈⛣᳜ࡢࡳ࡛࠶ࡿࠋࡑࡇ࡛➹⪅ࡽࡣࠊCKD ࡢ⑓ែゎᯒࡸ᪂ࡓ࡞἞⒪ἲ࡟ࡘ࠸࡚᫬㛫⑓ែ࣭᫬㛫๰⸆◊✲ࢆᐇ᪋ࡋࠊ᪂ࡓ࡞⭈⮚ࡢ⅖⑕ࡸ⥺⥔໬ࠊ⫢⮚ࡢ⸆≀௦ㅰᶵ⬟ࡢపୗᶵᵓࡸ CKD ࡢྜే⑕ࡢ୍ࡘ࡛࠶ࡿᚰ⮚ࡢ⅖⑕ᶵᵓࢆ᫂ࡽ࠿࡟ࡋࡓࠋࡉࡽ࡟ࠊࡇࢀࡽศᏊᶵᵓࢆᇶ┙࡟๰⸆ࢆᒎ㛤ࡋ࡚࠸ࡿࠋᮏ✏࡛ࡣࠊࡇࢀࡽࡢᢏ⾡ࢆᇶ┙࡜ࡋ࡚᫂ࡽ࠿࡟ࡋࡓ CKDࡢ⑓ែࠊ≉࡟་⸆ရࡢ㐺ṇ౑⏝࡟㛵ࡍࡿ◊✲࠾ࡼࡧ๰⸆◊✲ࡢどⅬ࠿ࡽ⤂௓ࡋࡓ࠸ࠋ ៏ᛶ⭈⮚⑓◊✲ࡢࡣࡌࡲࡾࡓሙྜࠊ⮚ჾࡀᑠࡉ࠸ࡇ࡜࠿ࡽࣔࢹࣝస〇࡟ᅔ㞴ࢆ᭷៏ᛶ⭈⮚⑓㸦chronic kidney disease: ௨ୗࠊCKD㸧ࡋࡓࠋᙜ᫬ࠊ஑ᕞ኱Ꮫ኱Ꮫ㝔⸆Ꮫ◊✲㝔⸆๣Ꮫศ㔝ࡢࡣࠊ⭈ᶵ⬟ࡀ៏ᛶⓗ࡟పୗࡋ࡚࠸ࡿ⥲⛠࡛࠶ࡿࡀࠊຓᡭ࡛࠶ࡗࡓᯇỌ┤ဢẶࡣࠊヨ⾜㘒ㄗࡢୖ࡟Ᏻᐃⓗ࡟CKD ᝈ⪅ࡣᮏ㑥࡛ 1330 ୓ே࡟ୖࡾ 8 ே࡟㸯ேࡀ

5/6Nx ࣐࢘ࢫࢆస〇ࡍࡿᢏ⾡ࢆぢฟࡋࠊࡼ࠺ࡸࡃ⑓ែCKD ࢆᝈࡗ࡚࠸ࡿ࡜᥎ᐃࡉࢀ࡚࠸ࡿࠋࡲࡓ CKD ࡣࡢศᏊᶵᵓࡢゎᯒࡀ㌶㐨࡟஌ࡾጞࡵࡓࠋ⭈ᶵ⬟ࡢ៏ᛶⓗ࡞పୗࡢࡳ࡞ࡽࡎࠊᵝࠎ࡞ྜే⑕ࢆేⓎࡍࡿࡇ࡜ࡶ▱ࡽࢀ࡚࠸ࡿࠋࡑࡢ୰࡛ࡶᴫ᪥᫬ィ࡜㛵 ៏ᛶ⭈⮚⑓ࡢ἞⒪࡟ࡘ࠸࡚㐃ࡀ῝࠸╧╀࡟ࡘ࠸࡚ࠊࡴࡎࡴࡎ⬮⑕ೃ⩌㸦ࣞࢫࢺࣞ⭈⮚ࡣ⏕࿨άື࡟క࠸⏕ࡌࡿ⪁ᗫ≀ࡢ᤼ἥࡸ⾑ᅽࢫࣞࢵࢢࢫ⑕ೃ⩌㸧࡞࡝࡟ࡼࡿ╧╀ࡢ㉁ࡢపୗࡸῶᑡ

ㄪᩚ࡞࡝ᵝࠎ࡞⮚ჾࢆ㐃ᦠࡋ࡚⏕యࡢᜏᖖᛶ⥔ᣢ࡟࡟ࡼࡿ╧╀㞀ᐖࡀ⮫ᗋ࡛ၥ㢟࡜࡞ࡗ࡚࠸ࡿ 1ࠋ➹⪅ࡣ㔜せ࡞ാࡁࢆࡋ࡚࠸ࡿࠋࡑࡢࡓࡵࠊCKD ᫬࡟ࡣᵝࠎ

2006 ᖺ࠿ࡽ CKD ᫬࡟࠾ࡅࡿ⭈⮚ࡸྜే⑕࡟ࡘ࠸࡚

࡞ྜే⑕ࡀ⏕ࡌࡿࠋ౛࠼ࡤ㧗⾑ᅽࠊᚰ୙඲࣭⫵Ỉ⭘ࠊ⮫ᗋ⸆Ꮫⓗ࡟㈉⊩࡛ࡁࡿࡇ࡜ࡣ࡞࠸࠿࡜⪃࠼ࠊᙜ᫬ࠊ㈋⾑ࠊ╧╀㞀ᐖࠊ⓶⭵⑕≧ࠊ㦵⢒㧼⑕࡞࡝ࡀᣲࡆࡽࢀ῭⏕఍㛗ᓮ⑓㝔╧╀་⒪ࢭࣥࢱ࣮㒊㛗࡛࠶ࡗࡓ㏆ࡿ 1ࠋࡋ࠿ࡋࡑࡢ୍᪉࡛ CKD ᫬ࡢ἞⒪࡜ࡋ࡚ࡣࠊኻ⸨ ⱥ᫂ ඛ⏕࡜ඹྠ◊✲ࢆ㐍ࡵ࡞ࡀࡽయෆ᫬ィ࡜ࢃࢀࡓ⭈⮚ᶵ⬟ࡢᅇ᚟ࡀ࡯࡜ࢇ࡝ぢ㎸ࡵ࡞࠸ࡓࡵࠊ⭈CKD ࡢ⑓ែ࡜ࡢ㛵㐃࡟ࡘ࠸࡚◊✲ࢆ㛤ጞࡋࡓࠋࡲࡎ⮚ᶵ⬟ࡢ⑓ែ㐍⾜ࢆண㜵ࡋ㏱ᯒ⒪ἲ࡬ࡢ⛣⾜ࢆ࡛ࡁࡣศᏊ⏕≀Ꮫⓗഃ㠃࠿ࡽゎᯒࢆ㐍ࡵࡿࡓࡵ࡟៏ᛶ⭈ࡿ㝈ࡾ㐜ࡽࡏࡿࡇ࡜ࡀ୺἞⒪ἲ࡜࡞ࡿࠋࡼࡗ࡚㣗஦⒪⮚⑓ࣔࢹࣝື≀ࡢ㑅ᐃ࠿ࡽጞࡵࠊࣄࢺࡢ CKD ⑓ែ࡟ἲࠊ⸆≀⒪ἲࠊ⾑ᾮί໬⒪ἲࡀᑐ⑕⒪ἲ࡜ࡋ࡚⾜ࢃࢀ㏆࠸ࣔࢹࣝ࡜ࡋ࡚⭈⮚ࢆ 5/6 ᦬ฟࡍࡿࡇ࡜࡟ࡼࡾస

࡚࠸ࡿ 3ࠋ

ᡂࡍࡿ CKD ࣔࢹࣝ 㸦5/6 Nephrectomy (5/6Nx)㸧࡟㣗஦⒪ἲ࡛ࡣࠊ༑ศ࡞࣮࢝ࣟࣜᦤྲྀࠊࢱࣥࣃࢡ㉁ࡢ

╔┠ࡋࡓࠋ5/6Nx ࡣࣛࢵࢺ࡛᪤࡟☜❧ࡉࢀࡓࣔࢹ࡛ࣝ

ไ㝈ࠊሷศไ㝈ࠊ࣒࣭࢝ࣜ࢘ࣜࣥࡢไ㝈ࠊ㐺ษ࡞Ỉศ࠶ࡾࠊᚎࠎ࡟⭈ᶵ⬟ࡀᝏ໬ࡍࡿᵝᏊࢆ⤒᫬ⓗ࡟ほᐹ࡛㔞ࡢᦤྲྀࡀ㔜せ࡜࡞ࡿࠋࡲࡓ⭈ᶵ⬟ࢆᨵၿࡉࡏࡿ⸆ࡀ

ࡁࡿ࡞࡝฼Ⅼࢆഛ࠼࡚࠸ࡓ 2ࠋࡋ࠿ࡋࣛࢵࢺ࡜ẚ㍑ࡋ

࡞࠸ࡓࡵࠊ㝆ᅽ⸆ࠊ฼ᒀ⸆ࠊࣜࣥ྾╔⸆ࠊ࣒࢝ࣜ࢘྾

㑇ఏᏊኚ␗ື≀ࡀከᙬ࡟Ꮡᅾࡍࡿ࣐࢘ࢫࢆᑐ㇟࡜ࡋ

╔⸆ࠊ࢚ࣜࢫ࣏࢚ࣟࢳࣥ〇๣ࠊࢫࢸࣟ࢖ࢻ࣭ච␿ᢚไ

‫ݩ‬ohdo@phar.kyushu-u.ac.jp᫬㛫⏕≀Ꮫ9RO1R 

ᅗ 1 Chronic kidney disease㸦CKD㸧᫬ࡢ⸆≀௦ㅰ⬟ࡢኚ໬ࠋᕥ㸸 CKD ᝈ⪅࡟࠾ࡅࡿྛ✀⸆≀ࡢ௦ㅰ⬟ࡢኚ໬ࢆ♧ࡍࠋ≉࡟⭈⮚௨እࡢ⮚ჾ࡟࠾ࡅࡿ௦ㅰ࡟ኚ໬ࡀㄆࡵࡽࢀࡿࡇ࡜࠿ࡽࠊ⸆≀἞⒪ࡢ㝿ࡣ⭈᤼ἥࡢࡳ࡞ࡽࡎ௚ࡢ⮚ჾࡢ௦ㅰ⬟ࡢኚ໬ࡶ༑ศ⪃៖ࡍ࡭ࡁ࡛࠶ࡿ 5ࠋྑ㸸5/6 ⭈⮚᦬ฟ (Nephrectomy:5/6Nx)࣐࢘ࢫ⫢⮚ࡢ࣐࢖ࢡࣟ࢔ࣞ࢖ࡢゎᯒ⤖ᯝࢆ♧ࡍࠋ࣐࢘ࢫࡢ⭈⮚࡟ 5/6Nx ฎ⨨ࡍࡿ࡜ࠊᚎࠎ
࡟ṧࡗࡓ⭈⮚ࡢᶵ⬟ࡀపୗࡍࡿࡇ࡜࡛ࣄࢺࡢ CKD ᵝࡢ⑓ែࢆ࿊ࡍࡿࠋ5/6Nx ࣐࢘ࢫ⫢⮚࡟Ⓨ⌧ࡍࡿ㑇ఏᏊࢆ࣐࢖ࢡࣟ࢔ࣞ࢖ゎᯒࡢࢹ࣮ࢱࢆᮏ࡟ࠊFunctional Annotation Tool DAVID Bioinformatics Resources 6.8, NIAID/NIH㸦https://david.ncifcrf.gov/summary.
jsp㸧࡟ࡼࡿࣃࢫ࢙࢘࢖ゎᯒࡋࡓ⤖ᯝࠊ⸆≀௦ㅰ࡟ಀࢃࡿ㑇ఏᏊࡢከࡃ࡟ኚ໬ࡀㄆࡵࡽࢀࡓ ࠋ๣ࠊ₎᪉⸆࡞࡝ࢆ౑ࡗ࡚ࠊ⭈⮚ࡢ⑓ែࡢ㐍⾜ࢆ㐜ࡽࡏࡢ࢖ࣥࢻ࢟ࢩࣝ◲㓟࡞࡝୍⯡ⓗ࡟ᒀẘ⑕≀㉁࡜࿧ࡤ

ࡿࡇ࡜ࡸྜే⑕ࡢ⑕≧ࢆ⦆࿴ࡍࡿࡇ࡜࡟㔜Ⅼࡀᙜ࡚ࢀࡿపศᏊࡀ௚⮚ჾࡢ⣽⬊࡟ᙳ㡪ࢆཬࡰࡋࠊ㑇ఏᏊⓎࡽࢀ࡚࠸ࡿࠋࡲࡓᮎᮇ⭈୙඲ࡢ἞⒪ἲ࡟ࡣࠊ⭈⮚ࡢാ⌧ࢆኚ໬ࡉࡏࡿࡇ࡜ࡀሗ࿌ࡉࢀ࡚࠸ࡓ 5ࠋࡁࡢ୍㒊ࢆ⿵࠺⭈௦᭰⒪ἲ࡜࿧ࡤࢀࡿ⾑ᾮ㏱ᯒࠊ⭡⭷㏱ᯒࠊࡑࡋ࡚᰿἞⒪ἲࡢ⭈⛣᳜ࡀ⾜ࢃࢀ࡚࠸ࡿࠋ⌧ᅾ⾜ࢃࢀ࡚࠸ࡿࡇࢀࡽࡢ୍㐃ࡢ CKD ἞⒪ࡢ୰࡛ࠊࡑࡇ࡛㔝⏕ᆺ 5/6Nx ࣐࢘ࢫࢆᑐ㇟࡟ࠊCKD ᫬࡟࡝ࡢࡼ࠺࡞㑇ఏᏊኚ໬ࡀ඲㌟࡛⏕ࡌ࡚࠸ࡿ࠿᳨ドࡍࡿࡓࡵ࡟ྛ⮚ჾࢆᑐ㇟࡟࣐࢖ࢡࣟ࢔ࣞ࢖ゎᯒࢆ⾜ࡗࡓ 6ࠋ⮫ᗋ⸆ᏛⓗどⅬ࠿ࡽ௓ධ࡛ࡁࡿࡢࡣ⸆≀἞⒪࡜࡞ࡿࡑࡢ⤖ᯝࠊ⫢⮚ࡢ⸆≀௦ㅰ࡟ಀࢃࡿ㑇ఏᏊࡢⓎ⌧ࡀኚࡀࠊ⭈⮚ࡸ⭈⮚እࡢ⮚ჾࡢ⸆≀௦ㅰ࣭᤼ἥᶵ⬟ࡢኚ໬ᐜࡋࠊࡑࡢከࡃࡀࣞࢳࣀ࣮ࣝ௦ㅰ㛵㐃㑇ఏᏊ࡛࠶ࡗࡓࠋࢆ⪃៖ࡋࡓ⸆≀౑⏝ࡢၥ㢟ࡸࠊᮍࡔ⭈ᶵ⬟ࡢᨵၿࡲࡓ≉࡟ࣄࢺࡢ cytochrome P450 3A4 (CYP3A4)࡟┦ᙜࡣಖㆤస⏝ࢆ♧ࡍ་⸆ရࡣஈࡋ࠸࡞࡝ࡢከࡃࡢ⮫ᗋࡍࡿศᏊ✀ࡢ 1 ࡘ࡛࠶ࡿ CYP3A11ࠊ࠾ࡼࡧࣞࢳࣀ࣮⸆Ꮫⓗㄢ㢟ࡀᾋࡁ᙮ࡾ࡜࡞ࡗ࡚࠸ࡓ㸦ᅗ 1㸧ࠋࡑࡇ࡛ࣝ௦ㅰࡢᚊ㏿㓝⣲ࡢ୍ࡘ࡛࠶ࡿ CYP26A1 ࡢⓎ⌧ࡀ➹⪅ࡣࠊࡇࢀࡽࡢၥ㢟ࢆゎỴࡍࡿࡓࡵ࡟⮫ᗋ⸆Ꮫⓗど኱ࡁࡃኚືࡋ࡚࠸ࡓࠋⅬ࠿ࡽ་⸆ရࡢ㐺ṇ౑⏝࡟㛵ࡍࡿ◊✲㸦⫱⸆㸧࣭๰⸆◊✲ࢆᐇ᪋ࡋࡓࠋ

ࡑࡇ࡛ 5/6Nx ࣐࢘ࢫࡢ⫢⮚࡟࠾ࡅࡿ CYP3A11ࠊ
CYP26A1 Ⓨ⌧పୗᶵᵓࢆゎᯒࡋࡓ⤖ᯝࠊࡇࢀࡽࡢ㓝⣲ࡢ㌿෗άᛶࡢపୗࡀࠊalbumin gene D-site binding៏ᛶ⭈⮚⑓᫬ࡢ་⸆ရ㐺ṇ౑⏝࡟㛵ࡍࡿ◊✲protein㸦DBP㸧ࢆ௓ࡋ࡚⏕ࡌ࡚࠸ࡿࡇ࡜ࡀ᫂ࡽ࠿࡟CKD ᝈ⪅࡟ᑐࡍࡿ⸆≀἞⒪࡟ࡣࠊ㝆ᅽ⸆ࢆጞࡵࠊ࡞ࡗࡓࠋCYP3A11 ࠾ࡼࡧ CYP26A1 ࡢⓎ⌧ࡣ㏻ᖖࠊᩘከࡃࡢ⸆๣ࡀ⏝࠸ࡽࢀࡿࠋࡋ࠿ࡋࠊ⭈ᶵ⬟ࡀపୗࡋ

DBP ࠾ࡼࡧ E4 promoter binding protein 4
㸦E4BP4㸧࡚࠸ࡿࡇ࡜࠿ࡽ౑⏝ୖὀពࡀᚲせ࡞⸆๣ࡶቑ࠼ࡿࠋ୺࡟ࡼࡾࣜࢬ࣑࢝ࣝ࡟ไᚚࡉࢀ࡚࠸ࡓࠋࡋ࠿ࡋ࡞ࡀࡽ࡟⭈⮚࠿ࡽయእ࡬᤼ἥࡉࢀࡿ⸆๣࡟ࡘ࠸࡚ࡣࠊCKD

5/6Nx ࣐࢘ࢫࡢ⫢⮚࡛ࡣ DBP ࡢⓎ⌧ࡀపୗࡋ࡚࠾ࡾࠊ᫬ࡢ⭈ᶵ⬟పୗ࡟ࡼࡾయෆ࡬ࡢ⸆≀⵳✚࡜๪స⏝ࡢࡇࢀ࡟క࠸ Cyp3a11ࠊCyp26a1 mRNA Ⓨ⌧㔞ࡣῶᑡቑຍࡣᐜ᫆࡟᝿ീࡀࡘࡃࠋࡑࡢ୍᪉࡛ࠊ⭈⮚௨እࡢ⮚ࡋ࡚ᴫ᪥ࣜࢬ࣒ࡢ᣺ᖜࡀపୗࡋ࡚࠸ࡓࠋࡋ࠿ࡋࡑࡢ୍ჾ࡛࠶ࡿ⫢⮚ࡸᑠ⭠࡞࡝ࡢ⸆≀௦ㅰ࣭᤼ἥ⬟ࡀኚᐜࡋ᪉࡛ࠊCKD ᫬࡟ DBP ࡢⓎ⌧ࡀపୗࡍࡿᶵᵓࡣ୙᫂⸆≀ࡢయෆືែ࡟␗ᖖࡀ⏕ࡌࡿࡇ࡜ࡀሗ࿌ࡉࢀ࡚࠸࡛࠶ࡗࡓࠋࡿ 4ࠋࡑࡢཎᅉ࡜ࡋ࡚ࠊ⭈⮚࠿ࡽᮏ᮶᤼ἥࡉࢀࡿࡣࡎ᫬㛫⏕≀Ꮫ9RO1R 

⏕యࡢᜏᖖᛶࡣࠊศᏊ-⣽⬊-⮚ჾ࡜୍㐃ࡢ㐃㛵ไᚚࡧࡘࡅࡿ◊✲ᡂᯝࡣࠊPubmed ᳨࡛⣴ࡋ࡚ࡶࣄࢵࢺࡏ

࡟ࡼࡾಖᣢࡉࢀ࡚࠸ࡿ 7ࠋࡲࡉ࡟యෆ᫬ィᶵᵓࡣࠊࡇࡎࠊᛴ࠸࡛ゎᯒࢆ㐍ࡵ࡚࠸ࡓ▮ඛ࡟ࠊ2008 ᖺ࡟ᮾிࡢ㐃㛵ไᚚࢆ㇟ᚩࡍࡿ⏕యᶵ⬟ࡢ୍ࡘ࡛࠶ࡿ 8ࠋయෆ኱Ꮫࡢ῝⏣ ྜྷᏕ ඛ⏕ࡽࡢࢢ࣮ࣝࣉࡀࠊTGF-ǃ ࠶ࡿ᫬ィࡢ࣐ࢫࢱ࣮ࢡࣟࢵࢡ࡛࠶ࡿど஺ཫୖ᰾ SCN ࠿ࡽ࠸ࡣ activin ࡜࠸࠺ࢱࣥࣃࢡ㉁ᅉᏊࡀ㠀ᖖ࡟ᙉ࠸᫬ィࡢಙྕࡣࠊ⚄⤒ࡸᾮᛶᅉᏊ࡛ྛ⣽⬊ࡸ⮚ჾࡢᴫ᪥ࣜࢬࣜࢭࢵࢺάᛶࢆᣢࡘࡇ࡜ࢆド᫂ࡋࡓ 10ࠋ࣒ࢆㄪᚊࡋ࡚࠸ࡿࡇ࡜ࢆࣄࣥࢺ࡟ࠊ⭈⮚࠿ࡽࡢఱ࠿ࡋ῝⏣ඛ⏕ࡽࡢ⦓ᐦ࡛⭾኱࡞◊✲ࢹ࣮ࢱ࡟ᅽಽࡉࢀࡽࡢಙྕࡀࠊ⭈⮚௨እࡢ௚ࡢ⮚ჾ࡬ఏࢃࡗ࡚࠸ࡿࡢ࡛

ࡓ୍᪉࡛ࠊTGF-ǃ ࡀ⅖⑕⮚ჾࡢ⭈⮚࡛ࡣ࡞࠸௚ࡢ⮚ࡣ࡞࠸࠿࡜௬ㄝࢆ❧࡚ࡓࠋࡑࡇ࡛ࡲࡎࠊ5/6Nx ࣐࢘ࢫჾࡢ᫬ィ㑇ఏᏊⓎ⌧࡟኱ࡁࡃᙳ㡪ࢆཬࡰࡍࡇ࡜ࢆᙉ

ࢆᑐ㇟࡟ CKD ࡢ⑓ែ㐍⾜࡟క࠸ቑຍࡍࡿ⾑୰ᅉᏊࢆࡃ♧၀ࡍࡿࢹ࣮ࢱ࡟Ᏻሚࢆឤࡌࡓࠋࡑࡇ࡛ࡉࡽ࡟⚾ࡓゎᯒࡋࡓࠋࡑࡢ⤖ᯝࠊ⑓ែ㐍⾜࡟క࠸⭈⮚࡛Ⓨ⌧ࡀቑࡕࡣゎᯒࢆ㐍ࡵࠊ⭈⮚ࡢ⅖⑕࡛Ⓨ⌧ࡀቑຍࡋࡓ TGF-

ຍࡍࡿ WUDQVIRUPLQJJURZWKIDFWRUǃ㸦TGF-ǃ㸧ࡀǃ1 ࡀ⾑ᾮࢆ௓ࡋ⫢⮚࡟స⏝ࡍࡿࡇ࡜࡛ DBP ࡢⓎ⌧ᙳ㡪ࢆཬࡰࡋ࡚࠸ࡿࡇ࡜ࢆぢฟࡋࡓࠋCKD ࡢ⑓ែ㐍㔞ࢆపୗࡉࡏࠊCYP3A11 ࠾ࡼࡧ CYP26A1 Ⓨ⌧㔞ࡢ⾜࡜ࡋ࡚ࠊึᮇࡣṧᏑࡍࡿࢿࣇࣟࣥࡀṇᖖ࡟ാࡁ⏕యῶᑡࢆࡶࡓࡽࡍࡇ࡜ࢆ᫂ࡽ࠿࡟ࡋࡓࠋࡲࡓࡇࢀࡽࡢෆࡢ⪁ᗫ≀ࢆᒀ࡟᤼ἥࡋ࡚࠸ࡿࡀࠊࡸࡀ࡚ࢿࣇࣟࣥࢆCYP Ⓨ⌧㔞ࡢపୗࡣࠊ⫢⮚࡟࠾ࡅࡿࣞࢳࣀ࣮ࣝࡢ௦ᵓᡂࡍࡿ⣽⬊ࡢ⑂ᘢ࡟ࡼࡾࢿࣇࣟࣥࡢ⬺ⴠࡀ㉳ࡇࡿࠋㅰ୙඲ࢆᘬࡁ㉳ࡇࡋࠊࡑࡢ⤖ᯝࠊ㧗ࣞࢳࣀ࣮ࣝ⾑⑕ࢆࡑࡢᚋࠊ⬺ⴠࡋࡓࢿࣇࣟࣥࡢ㛫㝽ࢆᇙࡵࡿࡓࡵ⥺⥔ⱆ⏕ࡌ࡚࠸ࡓࠋࡇࡢ⑕≧ࡣࣄࢺ CKD ᝈ⪅࡟࠾࠸࡚ࡶㄆ

⣽⬊ࡢቑຍ࡜ࡑࢀ࡟క࠺⭈⮚ࡢ⥺⥔໬ࡀ⏕ࡌࡿ 9ࠋࡇࡵࡽࢀࡿࡀ 11ࠊୖグ⤖ᯝࡣࡑࡢᶵᗎࡢ୍ࡘ࡜ࡋ࡚᫬ィࡢ⭈⮚ࡢ⥺⥔໬ࢆಁ㐍ࡍࡿᅉᏊࡢ୍ࡘࡀ TGF-ǃ ࡛㑇ఏᏊࢆ௓ࡋࡓ᪂ࡓ࡞ᶵᵓࢆ♧ࡋ࡚࠸ࡓࠋ⮫ᗋ࡛ࡣ⭈࠶ࡾࠊ⮫ᗋ࡟࠾࠸࡚ࡶ CKD ࡢࡳ࡞ࡽࡎ⫢⮚ࡸ⫵࡞࡝ᶵ⬟ࡸ⫢ᶵ⬟ࡢపୗࡋࡓ CKD ᝈ⪅࡟ᑐࡋ࡚ከࡃࡢᑐᵝࠎ࡞⮚ჾࡢ⥺⥔໬⑓ែ࡟㔜せ࡞ാࡁࢆ♧ࡍศᏊ࡛⑕⒪ἲ⸆ࡀฎ᪉ࡉࢀࡿࠋࡇࢀࡽࡢ་⸆ရࢆ CKD ᝈ⪅࠶ࡿࠋ╔┠ࡋࡓᙜ᫬ࠊTGF-ǃ ࡜ศᏊ᫬ィᶵᵓ࡜ࢆ⤖ࡀ᭹⏝ࡍࡿ㝿ࡣࠊࡼࡾ㐺ṇ࡞་⸆ရࡢ౑⏝᪉ἲࡀồࡵᅗ 2 Chronic kidney disease㸦CKD㸧᫬ࡢ⮚ჾ㐃㛵ᶵᵓ࡟╔┠ࡋࡓ⑓ែゎᯒ࡜๰⸆◊✲ࠋᕥ㸸Chronic kidney disease㸦CKD㸧࡟క࠺⭈⮚ࠊ⫢⮚ࡲࡓᚰ⮚ࡢ⑓ែࢆ♧ࡍࠋCKD ᫬ࡢ⭈⮚࡛Ⓨ⌧ࡀቑຍࡋࡓ TGF-ȕ ࡀ⾑ᾮࢆ௓ࡋ⫢⣽⬊࡟స⏝ࡍࡿ 6ࠋ⫢⣽⬊࡛ࡣࠊalbumin gene D-site binding protein㸦DBP㸧ࡢⓎ⌧పୗ࡟ࡼࡿ cytochrome P450s㸦CYPs㸧ࡢⓎ⌧ኚᐜࡀ⏕ࡌࠊ⾑ᾮ୰࡛ࡢࣞࢳࣀ࣮ࣝࡢ⵳✚ࢆࡶࡓࡽࡍࠋࡇࡢࣞࢳࣀ࣮ࣝࡢ⵳✚ࡣ⭈⮚ࡢ⣽⬊ࡢ CLOCK Ⓨ⌧㔞ࢆቑຍࡉࡏ
⅖⑕ࡢᝏ໬ࢆᘬࡁ㉳ࡇࡍࠋࡲࡓࣞࢳࣀ࣮ࣝࡣࠊ༢⌫ࡢ CLOCK/BMAL1 ࢆ௓ࡋ࡚ GPR68 Ⓨ⌧ࢆㄏᑟࡍࡿࠋGPR68 ࡢⓎ⌧ࡀ㧗࠸༢⌫ࡣᚰ⮚࡬ᾐ₶ࡍࡿࡇ࡜࡛ᚰ⮚ࡢ⅖⑕ࡸ⥺⥔໬ࢆ㐍⾜ࡉࡏࡿ 20ࠋࡍ࡞ࢃࡕࠊTGF-ȕ ࡟ࡼࡿ⭈-⫢㐃㛵ࠊࣞࢳࣀ࣮ࣝ࡟ࡼࡿ⫢-⭈㐃㛵࠾ࡼࡧ⫢-ᚰ㐃㛵ࢆ⤌ࡳྜࢃࡏ࡚ࠊ⭈-⫢-⭈ࡸ⭈-⫢-ᚰ㐃㛵ࡀ CKD ᫬࡟ࡣ⏕ࡌ࡚࠾ࡾࠊࡑࡢ㐣⛬࡛᫬ィ㑇ఏᏊࡀ㛵୚ࡋ࡚࠸ࡿࠋྑ㸸GPR68 ࢆᶆⓗ࡜ࡍࡿ๰⸆◊✲ࠋCKD ᫬ࡢᚰ⮚ࡢ⅖⑕ࢆᢚไࡍࡿ἞⒪⸆ࡣஈࡋ࠸ࠋ஑ᕞ኱Ꮫ኱Ꮫ㝔⸆Ꮫ◊✲㝔ࡀ᥎㐍ࡍࡿࢢ࣮ࣜࣥࣇ࢓࣐ࣝ๰⸆ࡢᢏ⾡ᇶ┙ࢆ฼⏝ࡋ࡚ࠊ໬ྜ≀ࣛ࢖ࣈ࣮ࣛࣜࡸ⸆⏝᳜≀ࣛ࢖ࣈ࣮ࣛࣜ࠿ࡽ GPR68 ࡢᶵ⬟㜼ᐖస⏝ࢆ♧ࡍ໬ྜ≀ࢆ᥈⣴ࠊྠᐃࡋࡓࠋ⌧ᅾࡶ࡞࠾⥅⥆ࡋ࡚◊✲ࢆ⾜ࡗ࡚࠾ࡾࠊࡼࡾᏳ඲࡛ᙉຊ࡞໬ྜ≀࡬࡜ᵓ㐀᭱㐺໬ࡍࡿ࡞࡝ࡋ࡚௻ᴗ࡜ࡢඹྠ◊✲ࢆᶍ⣴ࡋ࡚࠸ࡿࠋ᫬㛫⏕≀Ꮫ9RO1R ࡽࢀࡿࠋ5/6Nx ࣐࢘ࢫࡢゎᯒ࡟ࡼࡾᚓࡽࢀࡓ⫢⮚ࡢ⸆ೃ⿵࡜ࡋ࡚᭷ᮃ࡞໬ྜ≀ 9600 ಶࢆᑐ㇟࡟ࣁ࢖ࢫ࣮ࣝ≀௦ㅰᶵ⬟పୗ࡜⾑୰ࡢࣞࢳࣀ࣮ࣝ⃰ᗘୖ᪼ࢆ⤖ࡪࣉࢵࢺࢫࢡ࣮ࣜࢽࣥࢢࢆᐇ᪋ࡋࠊೃ⿵࡜࡞ࡿ G0s2 ⓎศᏊᶵᵓࡢ࢚ࣅࢹࣥࢫࡣࠊCKD ᫬ࡢ⫢⮚ࡢ௦ㅰ⬟ࢆ⌧ᢚไ໬ྜ≀ࢆᩘ✀ྠᐃࡋࡓࠋࡑࡢᚋࠊᇵ㣴⣽⬊ࢆ⏝♧ࡍ࢖࣐࣮࣮࢜࢝࡜ࡋ࡚⸆≀἞⒪࡟᭷⏝࡜⪃࠼ࡽࢀ࠸ࡓᏳ඲ᛶࢆ☜ㄆࡍࡿᐇ㦂ࡸ G0s2 ࡢ㌿෗࡟ᑐࡍࡿ≉ࡿࠋ␗ᛶࢆ☜ㄆࡍࡿᐇ㦂ࢆᐇ᪋ࡋࡓᚋ࡟ࠊೃ⿵໬ྜ≀ࡢ୰
࠿ࡽ 1 ࡘࢆ⤠ࡾ㎸ࢇࡔࠋࡉࡽ࡟ࡑࡢ໬ྜ≀ࡣࠊ஑ᕞ኱

៏ᛶ⭈⮚⑓ࡢ๰⸆◊✲⭈⮚ಖㆤ⸆ࡢ᥈⣴Ꮫ⸆Ꮫ◊✲㝔ࡢ᭷ᶵྜᡂᏛ⪅ࡢ⋤Ꮚ⏣ ᙲኵඛ⏕ࡽࡢ༠ຊࢆᚓ࡚ㄏᑟయ໬ࡋᵓ㐀᭱㐺໬ࡉࢀࠊ5/6Nx ࣐࢘ࢫᮍࡔ࡟⭈ᶵ⬟ࡢᨵၿࡲࡓࡣ⭈ᶵ⬟ࢆಖㆤࡍࡿ་⸆

ࡢ⭈⮚ࡢ⅖⑕ࡸ⥺⥔໬ࡀప⃰ᗘ࡛ᙉຊ࡟ᢚไࡉࢀࡿ

ရࡣஈࡋࡃࠊࡑࡢ࡯࡜ࢇ࡝ࡀᑐ⑕⒪ἲ⸆࡛࠶ࡿࠋࡑࡇ

ࡇ࡜ࡀㄆࡵࡽࢀࡓ 15ࠋࡑࡢᚋࠊ௻ᴗ࡜ࡢඹྠ◊✲࡟Ⓨ࡛ࡇࢀࡲ࡛ࡢ◊✲ᡂᯝࢆᇶ┙࡜ࡋ࡚ࠊ᪂ࡓ࡞స⏝ᶵᗎᒎࡋ᪤Ꮡࡢ་⸆ရ௨ୖࡢ⭈ಖㆤస⏝ࢆ♧ࡍ࡞࡝⏘Ꮫࢆ᭷ࡋࠊࡇࢀࡲ࡛ࡢ⭈ಖㆤ⸆ࡼࡾ᭷⏝࡞་⸆ရࡢ㛤Ⓨᐁ㐃ᦠ◊✲ࡢ᥎㐍࡟⮳ࡗ࡚࠸ࡿࠋ࡟ྥࡅ◊✲ࢆ㐍ࡵࡓ➹⪅ࡽࡣ㛗ࡽࡃࡀࢇࡢ⑓ែ࡜⸆ࡢຠᯝ๪స⏝࡟㛵ࡍࡿ◊✲ࢆ⾜ࡗ࡚࠸ࡓࡇ࡜࠿ࡽࠊࡀᚰ⮚ಖㆤ⸆ࡢ᥈⣴ࢇࡸ CKD ᫬࡟⏕ࡌࡿඹ㏻ࡢ⑓ែ࡜ࡋ࡚ㄆࡵࡽࢀࡿ៏CKD ࡛ࡣ⭈ࡢ⅖⑕࡟క࠺ྜే⑕ࡀከࡃㄆࡵࡽࢀࡿᛶ⅖⑕࡟╔┠ࡋ៏ᛶ⫢⅖࠿ࡽ⫢⮚ࡀࢇ࡟⮳ࡿ㐣⛬࡛ࡀࠊࡑࡢ୰࡛ࡶ⭈ᶵ⬟ࡢపୗ࡛⏕ࡌࡿ㧗⾑ᅽࡀᚰ⮚࡟ኚ໬ࡍࡿ㑇ఏᏊ࡜ࡋ࡚ G0/G1 Switch 2㸦G0s2㸧࡟ࡘ㈇ᢸࢆ࠿ࡅⓎ⑕ࡍࡿᚰ୙඲࡞࡝ᚰ⑌ᝈࡀࠊᮎᮇ CKD࠸࡚ゎᯒࢆ㐍ࡵࡓ 12ࠋG0s2 ࡣࠊࡀࢇࡢ⑓ែࡸච␿⣽ᝈ⪅ࡢṚᅉࡢୖ఩࡛࠶ࡿࠋࡋ࠿ࡋ᪤Ꮡ⸆࡛ࡣ CKD ᫬⬊ࡢᶵ⬟࡟㛵㐃ࡍࡿศᏊ࡜ࡋ࡚ぢฟࡉࢀ࡚࠸ࡓࡀࡢᚰ⑌ᝈࢆไᚚࡍࡿࡇ࡜ࡣᮍࡔ࡟㞴ࡋ࠸≧ἣ࡛࠶ࡿࠋ

13,14ࠊ➹⪅ࡽࡢ⊂⮬ࡢ◊✲࡟ࡼࡾࠊ⅖⑕ࡢቑᝏ࡟㛵ࢃ

ࡑࡇ࡛ CKD ࡟క࠺ᚰ⑌ᝈࡢ⑓ែゎᯒ࡜἞⒪⸆ࡢ㛤Ⓨࡿ nuclear factor-kappa B㸦NF-ǋǃ㸧࡜┦஫స⏝ࢆ♧ࢆ┠ᣦࡋ࡚◊✲ࢆ⾜ࡗࡓ㸦ᅗ 2㸧ࠋࡍࡇ࡜࡛ࠊ⅖⑕ࡢቑᝏ࡟┤᥋ⓗ࡟ᙳ㡪ࢆཬࡰࡍ࡜࠸࠺

╔┠ࡋࡓࡢࡣࠊᙜ᫬ࣉࣟࢺࣥឤཷᛶཷᐜయ࡜⪃࠼ࡽ᪂ࡓ࡞ᶵ⬟ࡀ᫂ࡽ࠿࡟࡞ࡗࡓࠋCKD ࡢཎᅉࡣࠊ⢾ᒀࢀ࡚࠸ࡓ 7 ᅇ⭷㈏㏻ᆺ G ࢱࣥࣃࢡ㉁ඹᙺཷᐜయࡢ 1⑓࡞࡝ከ✀ከᵝ࡛࠶ࡿࡀࠊࠕ⅖⑕ࠖࢆక࠺៏ᛶⓗ࡞⭈✀ G Protein-Coupled Receptor 68㸦GPR68㸧࡛࠶ࡿ⮚ࡢ⤌⧊㞀ᐖ࡜ᶵ⬟పୗࡣඹ㏻ࡍࡿ⑓ែ࡛࠶ࡿࠋࡑࡇ

16ࠋGPR68 ࡢⓎ⌧ࡣࠊṇᖖ࡞⾑⌫⣔⣽⬊࡟Ⓨ⌧ࡋ࡚࠸࡛ 5/6Nx ࣐࢘ࢫࢆᑐ㇟࡟᪂ࡓ࡞⅖⑕㛵㐃ศᏊ࡛࠶ࡿ

ࡿ୍᪉࡛ࠊ⅖⑕㒊఩ࡸࡀࢇ⤌⧊࡞࡝ࡢ⣽⬊࡟࠾࠸࡚ⓎG0s2 ࡢⓎ⌧ࢆᐃࡋࡓ⤖ᯝࠊ5/6Nx ࣐࢘ࢫࡢ⭈⮚࡟⌧ࡀቑຍࡍࡿࡇ࡜ࡀㄆࡵࡽࢀ࡚࠸ࡿࠋࡲࡓ㦵௦ㅰࡢ㡿࠾࠸࡚ࡶⓎ⌧ࡀቑຍࡍࡿࡇ࡜ࢆ᫂ࡽ࠿࡟ࡋࡓ 15ࠋࡉࡽᇦ࡛ࡣࠊ◚㦵⣽⬊ࡢศ໬࡟㔜せ࡞ᙺ๭ࢆᯝࡓࡋ࡚࠸ࡿ

࡟ G0s2siRNA ࡢᢞ୚࡟ࡼࡾ⭈⮚ࡢ⅖⑕ࡸ⥺⥔໬ࡀࡇ࡜ࡀ♧ࡉࢀ࡚࠸ࡿ 16ࠋ᭱㏆ࡢሗ࿌࡛ࡣࠊ⾑⟶ෆ⓶⣽ᢚไࡉࢀࡓࡇ࡜࠿ࡽࠊG0s2 ࡀ CKD ᫬ࡢ⭈⮚៏ᛶ⅖⬊࡟Ⓨ⌧ࡋ࡚⾑ὶࡢὶࢀ࡟క࠺ࡏࢇ᩿ᛂຊ࡟཯ᛂࡋ⑕⑓ែࡢቑᝏ࡟ᙳ㡪ࢆཬࡰࡍࡇ࡜ࡀ᫂ࡽ࠿࡟࡞ࡗࡓࠋ⾑⟶ᣑᙇ཯ᛂ࡟ᙳ㡪ࢆ୚࠼ࡿࡇ࡜ࡀ♧၀ࡉࢀࡿ࡞࡝ࠊ

G0s2 ࡢⓎ⌧ࢆᢚไࡍࡿࡇ࡜࡛⭈⮚ࡢ⅖⑕ࡢᢚไࡸ

ᑡࡋኚࢃࡗࡓᛶ㉁ࢆᣢࡘཷᐜయࢱࣥࣃࢡ㉁࡛࠶ࡿ 17ࠋᶵ⬟ࡢᨵၿࡀㄆࡵࡽࢀࡓࡇ࡜࠿ࡽࠊG0s2 ࡢᶵ⬟㜼ᐖ

CKD ࡛ࡣࠊ⾑ᾮ࡟ྵࡲࢀࡿࢱࣥࣃࢡ㉁ᡂศࡔࡅ࡛࡞

๣ࡸⓎ⌧ᢚไ๣ࡀ᪂ࡓ࡞ CKD ᫬ࡢ⭈ಖㆤ⸆࡟Ⓨᒎ࡛ࡃ㔠ᒓ࢖࢜ࣥᡂศࡸࡲࡓ㓟ᛶ≀㉁ࡢ⵳✚ࡀㄆࡵࡽࢀ

ࡁࡿࡢ࡛࡞࠸࠿࡜⪃࠼ࡓࠋࡋ࠿ࡋࡑࡢᙜ᫬ࡣࠊG0s2

࡚࠸ࡿ 18,19ࠋࡑࡇ࡛ CKD ᫬࡟ࣉࣟࢺࣥ࢖࢜ࣥࡢኚ໬ࡢᶵ⬟ࡸⓎ⌧ࢆ㜼ᐖࡍࡿ໬ྜ≀ࡣୡ⏺୰࡛ㄆࡵࡽࢀࡀ⏕ࡌ࡚ᚰ⾑⟶⣔ࡢ⅖⑕ࡸ㞀ᐖ࡟ GPR68 ࢆ௓ࡋᙳ㡪࡞࠿ࡗࡓࡓࡵࠊᅜ❧◊✲㛤Ⓨἲே᪥ᮏ་⒪◊✲㛤Ⓨᶵࢆཬࡰࡋ࡚࠸ࡿࡢ࡛࡞࠸࠿࡜௬ㄝࢆ❧࡚◊✲ࢆ㛤ጞᵓ㸦AMED㸧ࡢᨭ᥼ࡢୗ࡛ࠊ஑ᕞ኱Ꮫ኱Ꮫ㝔⸆Ꮫ◊✲ࡋࡓࠋ㝔࡛⾜ࢃࢀ࡚࠸ࡿࢢ࣮ࣜࣥࣇ࢓࣐ࣝ๰⸆ࡢᢏ⾡ᨭ᥼

5/6Nx ࣐࢘ࢫࢆᑐ㇟࡟ GPR68 mRNA Ⓨ⌧㔞ࢆࢆཷࡅ࡚ G0s2 ࡢⓎ⌧ᢚไ๣ࡢ᥈⣴࡜ᵓ㐀᭱㐺໬ࢆ⾜ᐃࡋࡓ⤖ᯝࠊ5/6Nx ࡢᚰ⮚࡛Ⓨ⌧ࡀቑຍࡋ࡚࠸ࡓࠋࡑ

ࡗࡓࠋG0s2 ࡢᶵ⬟㜼ᐖ๣ࢆ᥈⣴ࡍࡿ⣔ࢆᵓ⠏ࡍࡿࡇࡇ࡛ GPR68 ࡢ㌿෗ไᚚ㡿ᇦࢆࢹ࣮ࢱ࣮࣋ࢫᇶ࡟ㄪᰝ࡜ࡀ㠀ᖖ࡟ᅔ㞴ࢆᴟࡵࡓࡓࡵࠊDNA ࢆ㗪ᆺ࡟ G0s2ࡋࡓ⤖ᯝࠊዲ㒔ྜ࡟ࡶ E-box ࡀㄆࡵࡽࢀࡓࡇ࡜࠿ࡽࡢ㌿෗ㄪ⠇㡿ᇦࢆࢡ࣮ࣟࢽࣥࢢࡋࠊࡉࡽ࡟ G0s2 ࣉࣟ᫬ィ㑇ఏᏊ࡜ࡢ㛵㐃ᛶ࡟╔┠ࡋࡓࠋ㔝⏕ᆺ࠾ࡼࡧ࣮ࣔࢱ࣮࡛ࣝࢩࣇ࢙࣮ࣛࢮ㑇ఏᏊࡀⓎ⌧ࡍࡿ⣽⬊ࢆ

Clock mutant㸦Clk/Clk㸧࣐࢘ࢫࢆᑐ㇟࡟ 5/6Nx ฎ⨨స〇ࡋࡓࠋస〇ࡋࡓ⣽⬊ࢆᑐ㇟࡟ࠊᮾி኱Ꮫࡢ๰⸆ᶵ

ࡋࠊᚰ⮚ࡢ⑓ែࢆゎᯒࡋࡓ 20 ࠋࡑࡢ⤖ᯝࠊ Clk/Clkᵓࡀᡤ᭷ࡋ࡚࠸ࡓᙜ᫬ࡢ⣙ 20 ୓໬ྜ≀ࡢ࠺ࡕ་⸆ရ

5/6Nx ࣐࢘ࢫ࡜㔝⏕ᆺ 5/6Nx ࣐࢘ࢫ࡛ࠊ⾑ᅽࡸ⾑୰᫬㛫⏕≀Ꮫ9RO1R 

࢔ࣥࢪ࢜ࢸࣥࢩࣥ II ್➼࡟ᕪ␗ࡣ࡞࠿ࡗࡓ࡟ࡶ࠿࠿CKD ᝈ⪅⏤᮶ࡢ⾑Ύࢆᑐ㇟࡟ゎᯒࡋࡓ⤖ᯝࠊCKD ᝈࢃࡽࡎࠊClk/Clk 5/6Nx ࣐࢘ࢫࡢࡳࠊᚰ⥺⥔໬ࡸᚰ୙⪅࡟࠾࠸࡚⾑୰ࣞࢳࣀ࣮ࣝ/RBP4 ࡢ⵳✚ࡀㄆࡵࡽࢀ

඲࣐࣮࣮࡛࢝࠶ࡿ brain natriuretic peptide㸦BNP㸧ࡓࠋࡑࡇ࡛ࡇࡢ⾑Ύࢆࣄࢺ༢⌫࡟᭚㟢ࡋ GPR68ࠊ

್ࡢୖ᪼ࡀᢚไࡉࢀࡓࠋࡇࡢཎᅉ㑇ఏᏊ࡟ࡘ࠸࡚࣐࢖

CLOCKࠊBMAL1 Ⓨ⌧࠾ࡼࡧ⅖⑕ᛶࢧ࢖ࢺ࢝࢖ࣥ⏘ࢡࣟ࢔ࣞ࢖ゎᯒ➼ࢆᐇ᪋ࡋゎᯒࡋࡓ⤖ᯝࠊ4 ✀ࡢೃ⿵⏕㔞ࢆ㑇ఏᏊࡀᢳฟࡉࢀࡓࠋࡑࡢ୰࡟അ↛࡟ࡶ GPR68 ࡀྵ⾑୰ࡢࣞࢳࣀ࣮ࣝ/RBP4 ⃰ᗘ࡜ṇࡢ┦㛵ࢆ♧ࡋࡓࠋࡲࢀ࡚࠸ࡓࠋࡑࡇ࡛ CKD ࡢᚰ⮚ࡢ⑓ែ࡟࡝ࡢࡼ࠺࡟

ࡲࡓᝈ⪅ࡢᚰᶵ⬟ࡢ⛬ᗘࢆ♧ࡍ BNP ್࡟ࡘ࠸࡚ࡶࠊ

࠿࠿ࢃࡿ࠿ㄪ࡭ࡿࡓࡵ࡟ GPR Ⓨ⌧⣽⬊ࡢྠᐃࢆヨࡳ

GPR68 Ⓨ⌧ࡸࣞࢳࣀ࣮ࣝ/RBP4 ⃰ᗘ࡜ṇࡢ┦㛵ࢆ♧ࡓࠋࡑࡢ⤖ᯝࠊ5/6Nx ࣐࢘ࢫࡢᚰᐊ࡟ᾐ₶ࡋࡓ༢⌫⏤ࡋ ࡓ ࠋ ௨ ୖ ࡢ ⤖ ᯝ ࠿ ࡽ ࠊ ࣞ ࢳ ࣀ ࣮ ࣝ /RBP4- ༢ ⌫᮶࣐ࢡࣟࣇ࢓࣮ࢪ࡟㧗Ⓨ⌧ࡋ࡚࠾ࡾࠊ༢⌫࠿ࡽࡢ⅖⑕

CLOCK/BMAL1-GPR68 ࢆ㍈࡟ࡋࡓ᪂ࡓ࡞⭈-ᚰ㐃㛵ᛶࢧ࢖ࢺ࢝࢖ࣥ⏘⏕࡟㛵୚ࡋ࡚࠸ࡓࠋࡉࡽ࡟ࠊGPR68

ࡀ᫂ࡽ࠿࡟࡞ࡗࡓࠋ

ᐃࡋࡓࠋࡑࡢ⤖ᯝࠊྛᅉᏊࡢⓎ⌧ࡸ⏘⏕㔞ࡣ㧗Ⓨ⌧༢⌫ࡣ⭁⮚࡟㈓ⶶࡉࢀ࡚࠸ࡓࡇ࡜࠿ࡽࠊ࣐࢘ࢫ

GPR68 ࡀ CKD ᫬ࡢᚰ⮚ࡢ⅖⑕ࡸ⥺⥔໬ࡢቑᝏ࡟ࢆᑐ㇟࡟⭁⮚᦬ฟࢆ⾜ࡗࡓ࡜ࡇࢁࠊᚰᐊ୰ GPR68 㧗ᙳ㡪ࢆཬࡰࡍࡇ࡜ࡀ᫂ࡽ࠿࡟࡞ࡗࡓࡇ࡜࠿ࡽࠊCKDⓎ⌧⣽⬊ᩘࡢῶᑡࡀ☜ㄆࡉࢀࡓࠋࡑࡇ࡛⭁⮚᦬ฟࡢྜే⑕ࡢ἞⒪⸆࡟ࡘ࠸࡚๰⸆ᒎ㛤ࢆヨࡳࡓࠋCKD5/6Nx ࣐࢘ࢫ࡟ᑐࡋ࡚ṇᖖ༢⌫ࡲࡓࡣ GPR68 ࢆࣀࢵᝈ⪅ࡢࣞࢳࣀ࣮ࣝ⵳✚ࢆᢚไࡍࡿࡇ࡜ࡀᚰ⮚ࡢ⅖⑕ࢡࢲ࢘ࣥࡋࡓ༢⌫ࢆ⛣᳜ࡋࡓ࡜ࡇࢁࠊṇᖖ༢⌫⛣᳜⩌ࢆᢚ࠼ࡿᡭࡗྲྀࡾ᪩࠸἞⒪࡛࠶ࡿࡀࠊయෆ࡟࠶ࡿࣞࢳ࡛ࡣᚰ⥺⥔໬ࡸ BNP ್ࡢୖ᪼ࡀㄆࡵࡽࢀࡓࡢ࡟ᑐࡋࠊࣀ࣮ࣝࡢከࡃࡣ㣗஦⏤᮶࡛࠶ࡾࠊᵝࠎ࡞㣗≀࡟ྵࡲࢀ

GPR68 ࣀࢵࢡࢲ࢘ࣥ༢⌫⛣᳜⩌࡛ࡣࡇࢀࡽࡢୖ᪼ࡀࡿࣞࢳࣀ࣮ࣝ㸦ࣅࢱ࣑ࣥ A㸧ࢆ㣗஦ไ㝈ࡼࡾไᚚࡍࡿᢚ ไ ࡉ ࢀ ࠊ CKD ᫬ ࡟ ࠾ ࡅ ࡿ ᚰ ⮚ ࡢ ⑓ ែ ࡢ ቑ ᝏ ࡟ࡇ࡜ࡣᅔ㞴ࢆᴟࡵࡿࡇ࡜ࡀ᝿ᐃࡉࢀࡓࠋࡑࡇ࡛

GPR68 ࡀ㛵୚ࡋ࡚࠸ࡿࡇ࡜ࡀ᫂ࡽ࠿࡟࡞ࡗࡓࠋ

GPR68 ࡢᶵ⬟࡟┤᥋ⓗ࡟ᙳ㡪ࢆཬࡰࡍ໬ྜ≀࡟ࡘ࠸ࡑࡢ୍᪉࡛ࠊCKD ᫬࡟༢⌫࡛ GPR68 ࡢⓎ⌧ࡀቑ࡚ㄪᰝࡋࡓ⤖ᯝࠊGPR68 ࡢᶵ⬟ࢆάᛶ໬ࡍࡿ໬ྜ≀ຍࡍࡿᶵᵓࡣ୙࡛᫂࠶ࡗࡓࡓࡵࠊࡑࡢᶵᵓࢆ᫂ࡽ࠿࡟

ࡣ≉チฟ㢪ࡉࢀ࡚࠸ࡓࡀࠊ㜼ᐖࡍࡿ໬ྜ≀ࡢሗ࿌ࡣㄆࡍࡿࡓࡵࡢ◊✲ࢆ⾜ࡗࡓࠋࡲࡎ╔┠ࡋࡓࡢࡣࠊCKD ᫬ࡵࡽࢀ࡞࠿ࡗࡓࡇ࡜࠿ࡽࠊGPR68 ࡢᶵ⬟ࢆᢚไࡍࡿ࡟Ⓨ⑕ࡍࡿ㧗ࣞࢳࣀ࣮ࣝ⾑⑕࡛࠶ࡿࠋࣞࢳࣀ࣮ࣝࡢᶆ໬ྜ≀ࡢ᥈⣴࡟ᡓ␎ࢆኚ᭦ࡋࡓࠋࡲࡓᙜ᫬ࠊపศᏊࡢⓗศᏊ࡜ ࡋ࡚᰾ ෆࣞࢭ ࣉ ࢱ࣮࡜ࡋ ࡚ാࡃ retinoic᫬௦ࡣ⤊ࢃࡾ୰ศᏊࡢ᫬௦࡟✺ධ࡞࡝ࠊ་⸆ရࡢࣔࢲ

acid receptor㸦RAR㸧࡞࡝ࡀ᭷ྡ࡛࠶ࡿࡀࠊࣞࢳࣀ࣮ࣜࢸ࢕㠉࿨ࡀ⾜ࢃࢀ࡚࠸ࡓࡇ࡜࡟ឤ໬ࡉࢀࠊపศᏊ࡛ࣝࡣ⾑ᾮ୰࡛ࡣࣞࢳࣀ࣮ࣝ/retinol binding protein 4ࡣ㞴ࡋ࠸࡜ࡉࢀࡿ GPCR ࡢᶵ⬟㜼ᐖ໬ྜ≀ࢆ୰ศᏊ

㸦RBP4㸧」ྜయࢆᙧᡂࡋࠊᶆⓗ⣽⬊ࡢ⣽⬊⭷࡟Ⓨ⌧ࡀྵࡲࢀࡿ⸆⏝᳜≀ࣛࣈ࣮ࣛࣜ࠿ࡽ᥈⣴ࡍࡿࡇ࡜ࢆ

ࡍࡿ stimulated by retinoic acid 6㸦STRA6㸧࡟స⏝ヨࡳࡓࠋࡋ࡚⣽⬊ෆ࡬㍺㏦ࡉࢀࡿ࡜ඹ࡟ STRA6 ࢆάᛶ໬ࡋࠊᅜ❧◊✲㛤Ⓨἲே་⸆ᇶ┙࣭೺ᗣ࣭ᰤ㣴◊✲ᡤࡀᡤsignal transducer and activator of transcription

᭷ࡍࡿ 8008 ✀ࡢ⸆⏝᳜≀࢚࢟ࢫࡢࣛ࢖ࣈ࣮ࣛࣜࢆᑐ

㸦STAT㸧ࡢࣜࣥ㓟໬ࢩࢢࢼࣝࡀάᛶ໬ࡍࡿࡇ࡜ࡀ▱㇟࡟ࣁ࢖ࢫ࣮ࣝࣉࢵࢺࢫࢡ࣮ࣜࢽࣥࢢࢆᐇ᪋ࡋࡓࠋ

ࡽࢀ࡚࠸ࡿ 21ࠋࡉࡽ࡟༢⌫ࡢከࡃࡣ⭁⮚࡟⵳࠼ࡽࢀ⾑

GPR68 ࡢάᛶ໬࡟ࡼࡿࢩࢢࢼࣝࡣ Nuclear factor ofᾮࢆ௓ࡋ࡚⑓ᕢ࡟ྥ࠿࠺ࡇ࡜ࡀ᝿ᐃࡉࢀࡓࡇ࡜࠿ࡽࠊ

activated T-cells㸦NFAT㸧ࡢࣜࣥ㓟໬࠾ࡼࡧ NFAT ࡟CKD ᫬ࡢ༢⌫࡜㧗ࣞࢳࣀ࣮ࣝ⾑⑕࡜ࡢ㛵㐃ᛶ࡟↔Ⅼࡼࡿ㌿෗άᛶࢆಁ㐍ࡍࡿ 22ࠋࡑࡇ࡛ NFAT ࡟ࡼࡿ㌿ࢆᙜ࡚ࡓࠋ෗άᛶ໬ࢆᣦᶆ࡜ࡋࡓ GPR68 ࡢᶵ⬟㜼ᐖ໬ྜ≀᥈⣴ࡲࡎึࡵ࡟ࠊ5/6Nx ࣐࢘ࢫ࡟ᑐࡋ࡚⾡ᚋ 8-14 㐌ࡢ࡟ࢫࢡ࣮ࣜࢽࣥࢢ⣔ࢆᵓ⠏ࡋࠊྛ✀⸆⏝᳜≀࢚࢟ࢫࡢ㛫࡟ࣞࢳࣀ࣮ࣝ୙ྵ⤥㣵ࢆ⾜ࡗࡓࠋࡑࡢ⤖ᯝࠊ⾑୰ࣞຠᯝࢆホ౯ࡋࡓࠋࡑࡢ⤖ᯝࠊᩘ✀ࡢ࢚࢟ࢫࡀྠᐃࡉࢀࠊ

ࢳࣀ࣮ࣝ/RBP4 ࡢ⵳✚ࠊ༢⌫୰ࡢ GPR68ࠊCLOCKࠊࡑࡢ୰࡛ࡶ GPR68 ࡟ᑐࡍࡿ㑅ᢥᛶ࡜ᙉ࠸㜼ᐖຠᯝࢆ

BMAL1 ࡢⓎ⌧ୖ᪼࠾ࡼࡧ BNP ್ࡢቑຍࡀᢚไࡉࢀ♧ࡍ࢚࢟ࢫ㸡2 ࢆぢฟࡋࡓࠋࡑࡇ࡛ CKD ࣔࢹ࣐ࣝ࢘ࡓࠋࡲࡓࠊࣄࢺึ௦ᇵ㣴༢⌫࡟࠾࠸࡚ࡶ GPR68 Ⓨ⌧ࢫࡢᚰ⮚ࡢ⅖⑕࡟ཬࡰࡍ࢚࢟ࢫ㸡2 ࡢᙳ㡪ࢆ☜ㄆࡋࡣࣞࢳࣀ࣮ࣝ/RBP4 ࢆ௓ࡋࡓ CLOCK/BMAL1 ࡟ࡼࡓ⤖ᯝࠊ࢚࢟ࢫ㸡2 ࡢᢞ୚࡟ࡼࡾᚰ⮚ࡢ⅖⑕ࡸ⥺⥔໬ࡿࢺࣛࣥࢫάᛶ໬࡟ࡼࡾไᚚࡉࢀ࡚࠸ࡓࠋࡉࡽ࡟㏆⸨ࡀᢚไࡉࢀࡓࠋ᭦࡟࢚࢟ࢫ㸡2 ࡢ୺ᡂศࢆ᥈⣴ࡋࡓ⤖ඛ⏕ࡸ஑ᕞ኱Ꮫ⑓㝔ᚠ⎔ჾෆ⛉ ⟄஭ ⿱அ ᩍᤵࠊ஭ᯝࠊ໬ྜ≀ A ࢆྠᐃࡋࡓࠋ⌧ᅾࠊ≉チฟ㢪ࡍࡿ࡜ඹ࡟ᡭ ཭⨾ ෸ᩍᤵࠊ஑ᕞ኱Ꮫ኱Ꮫ㝔⸆Ꮫ◊✲㝔ࡼࡾ⸆ຠࡢᙉ࠸໬ྜ≀࡬࡜ᵓ㐀᭱㐺໬ࢆヨࡳࡘࡘ௻ࢢ࣮ࣟ

࢝ࣝ࣊ࣝࢫࢣ࢔ศ㔝 ᑠᰗ ᝅ ᩍᤵࡢ༠ຊࡢୗ࡛᫬㛫⏕≀Ꮫ9RO1R ᴗ࡜ࡢඹྠ◊✲࡟ྥࡅ༠㆟ࢆࡋ࡚࠸ࡿࠋ



guideline for the treatment of chronic kidney࠾ࢃࡾ࡟

disease. Clin. Exp. Nephrol. 13, 533-566 (2009).

ᮏ㡯࡛ࡣ➹⪅ࡀࠊCKD ࡢ⑓ែ࡜ศᏊ᫬ィࡢ㛵ಀ࡟╔┠ࡋ◊✲ࡢ❧ࡕୖࡆ࠿ࡽ⌧ᅾ࡟࠸ࡓࡿࡲ࡛ࡢ㌶㊧4.

Dreisbach, A. W. et al. The effect of chronicࢆ⸆ရࡢ㐺ṇ౑⏝࡜๰⸆ࡢどⅬ࡟ศࡅ࡚㏙࡭ࡓࠋ

renal failure on drug metabolism and transport.

CKD ࡣ⌧ᅾࡶ࡞࠾࢔࣓ࣥࢵࢺ࣓ࢹ࢕࢝ࣝࢽ࣮ࢬࡀ㧗

Expert. Opin. Drug Metab. Toxicol. 4, 1065-ࡃࠊᑐ⑕⒪ἲ࡟ࡣከࡃࡢ⸆๣ࡢ᭹⏝ࡀᚲせ࡜ࡉࢀ࡚࠸1074 (2008).

ࡿࠋCKD ᝈ⪅࡟⸆๣ࢆ⏝࠸ࡿሙྜࠊ⭈᤼ἥᆺࡢ⸆≀5.

cytochrome P450-mediated drug metabolism.

ࡢ౑⏝᫬ࡔࡅ࡛࡞ࡃࠊ⫢⮚ࡸ௚ࡢ⮚ჾ࡛௦ㅰࡉࢀࡿ⸆

Adv. Chronic. Kidney Dis. 23, 67-75 (2016).

≀࡟ࡘ࠸࡚ࡶ౑⏝᫬ࡣὀどࡋ࡞ࡅࢀࡤ࠸ࡅ࡞࠸ࠋࡋ࠿
ࡋࡇࢀࡲ࡛ࠊCKD ᫬࡟࠾ࡅࡿ⫢⮚ࡢ⸆≀௦ㅰ⬟ࡢኚ

Ladda, M. A. et al. The effects of CKD on

6.

Hamamura, K. et al. Alterations of hepatic໬ࢆホ౯ࡍࡿ᭷⏝࡞ࣂ࢖࣐࣮࣮࢜࢝ࡣⓙ↓࡛࠶ࡗࡓࠋ

metabolism in chronic kidney disease via D-boxࡑࡢ୰࡛ࠊ➹⪅ࡽࡢ◊✲࡟ࡼࡾぢฟࡋࡓ⾑୰ࣞࢳࣀ࣮bindingࣝࡢ⃰ᗘኚ໬ࢆᣦᶆ࡟ࡍࡿࡇ࡜ࡣࠊCKD ᝈ⪅ࡢᢞ⸆

dysfunction. J. Biol. Chem. 291, 4913-4927

タィ࡟ࡶ฼⏝ྍ⬟࡛࠶ࢁ࠺ࠋࡲࡓ㧗ࣞࢳࣀ࣮ࣝ⾑⑕ࡀࠊ

(2016).

⭈⮚ࡸᚰ⮚ࡢ⑓ែࢆᝏ໬ࡉࡏࡿ࡜࠸࠺ࠕ⭈-⫢-⭈㐃㛵ࠊ

7.

aggravate

therenalRué, P. et al. Cell dynamics and gene expression
control in tissue homeostasis and development.

⭈-⫢-ᚰ㐃㛵ࠖ࡜࠸ࡗࡓ⑓ែ࡟ᇶ࡙ࡃ໬ྜ≀ࢫࢡ࣮ࣜ

Mol. Syst. Biol. 11,792 (2015).

ࢽࣥࢢ࡟ࡼࡾぢฟࡋࡓࢩ࣮ࢻ໬ྜ≀ࢆࠊࡉࡽ࡟㧗ᗘ໬ࡋ࡚᪂ࡓ࡞἞⒪⸆ࡢ㛤Ⓨ࡟Ⓨᒎࡉࡏࡓ࠸࡜⪃࠼࡚࠸

protein

8.

Kim, P. et al. Coupling the Circadian Clock toHomeostasis: The Role of Period in Timingࡿࠋࡇࢀࡽ୍㐃ࡢ⑓ែᶵᵓࡣࠊCKD ࡢࡳ࡞ࡽࡎ௚ࡢ៏ᛶ⅖⑕ᛶࡢ⑌ᝈ㡿ᇦ࡟࠾࠸࡚ࡶᛂ⏝ྍ⬟࡛࠶ࡿ࡜

Physiology. Endocrine Reviews. 40, 66–95⪃࠼ࡽࢀࡿࡓࡵࠊᵝࠎ࡞་⒪ࡢⓎᒎ࡟ࡘ࡞ࡀࡿࡇ࡜ࡀ

(2019).

ᮇᚅࡉࢀࡿࠋࡉࡽ࡟⮚ჾ㐃㛵ࡣࡶ࡜ࡼࡾ⣽⬊㐃㛵࡟ࡶศᏊ᫬ィࡣ㔜せ࡞ᙺ๭ࢆᯝࡓࡍࠋ௒᪥ࡶ࡞࠾࢔࣓ࣥࢵࢺ࣓ࢹ࢕࢝ࣝࢽ࣮ࢬࡢ㧗࠸⑌

9.

Xiao-Ming, M. et al. TGF-ǃ WKH PDVWHU
regulator of fibrosis. Nat. Rev. Nephrol. 12, 325338 (2016).

ᝈࡣᩘከࡃ࠶ࡾࠊయෆ᫬ィ࡜ࡢ㛵㐃ᛶࡶᮍ▱ᩘ࡛࠶ࡿࠋ

10. Kon N. et al. Activation of TGF-beta/activin➹⪅ࡣࠊࡇࡢㄢ㢟ゎỴ࡟࠾࠸࡚ୡ⏺࡟ඛ㥑ࡅࡿࡓࡵࠊ

signalling resets the circadian clock throughࢡࣟࣀࢣ࣑࢝ࣝࣂ࢖࢜ࣟࢪ࣮ᢏ⾡㸦໬ྜ≀࡜཯ᛂ-᫬

rapid induction of Dec1 transcripts. Nat. Cell.

㛫-ᒁᅾ࡟╔┠ࡋࡓ᫬✵㛫ゎᯒᢏ⾡㸧ࢆ㥑౑ࡋ࡚ࠊ໬ྜ

Biol. 10, 1463-1469 (2008).

≀࡟ࡼࡿ᫬ィ㑇ఏᏊࡢ㞀ᐖࠊ᧯సࠊデ᩿ᢏ⾡ࡢᵓ⠏࡟

11. Jing, J. et al. Chronic kidney disease altersᡂຌࡋ࡚࠸ࡿࠋࡇࡢᢏ⾡ࢆά⏝ࡋࠊ⑓ែ࡜㛵㐃ࡋࣜࢬvitamin a homeostasis via effects on hepatic࣑࢝ࣝ࡟ᶵ⬟ࡋ࡚࠸ࡿᶆⓗศᏊࢆᑐ㇟࡜ࡋࡓ἞⒪⸆

rbp4 protein expression and metabolic enzymes.

ࢩ࣮ࢬ໬ྜ≀ࡢྠᐃ࡟ຍ࠼࡚ࠊගࠊ⸆ࡸᰤ㣴⣲ࠊᚤᙅ

Clin Transl Sci. 9, 207–215 (2016).

㟁ὶ࡛ศᏊ᫬ィࢆไᚚࡋࠊ✀ࠎࡢ⑌ᝈ࡟ຠᯝⓗ࡛࠶ࡿ

12. Ohdo S, Koyanagi S, and Matsunaga N.

ࡇ࡜ࡶ᫂ࡽ࠿࡟ࡋ࡚࠸ࡿࠋ௒ᚋࡶࡼࡾ῝ᗘࢆቑࡋࡓ⑓Chronopharmacological strategies focused onែゎᯒࢆ㐍ࡵ࡚ࠊ⮫ᗋ⸆Ꮫ◊✲⪅࡜ࡋ࡚⮫ᗋ࡟ᙺ࡟❧chrono-drugࡘ◊✲ࢆ᥎㐍ࡋࡓ࠸࡜⪃࠼࡚࠸ࡿࠋ

discovery.

Pharmacol.

Ther.

202,72-90 (2019).
13. Cristillo, A. D. et al.

Cyclosporin A inhibits

early mRNA expression of G0/G1 switch gene 2ཧ⪃ᩥ⊩(G0S2) in cultured human blood mononuclear

1.

Romagnani, P. et al. Chronic kidney disease2.

Kuczera, M. et al. Local angiotensin formation

cyclin A1 hypermethylation and p53 mutationin hindlimbs of uremic hypertensive andin head and neck cancer identified by reversal

renovascular hypertensive rats. J. Hypertens. 9,of epigenetic silencing Cancer Res. 64, 5982-41-48 (1991).

5987 (2004).

Nat. Rev. Dis. Primers. 23, 17088 (2017).

3.

Sasaki, S. et al. Evidence-based practice

cells. DNA Cell Biol. 16, 1449-1458 (1997).
14. Tokumaru, Y. et al. Inverse correlation between

15. Matsunaga, N. et al. Inhibition of G0/G1 switch᫬㛫⏕≀Ꮫ9RO1R 2 ameliorates renal inflammation in chronic

20. Yoshida, Y. et al. Alteration of circadiankidney disease. eBioMedicine. 13, 262-273

machinery in monocytes underlies chronic(2016).

kidney16. Nayak, A. P. et al. The proton-sensing receptor
ovarian cancer G-protein coupled receptor 1(OGR1) in airway physiology and disease. Curr.

Opin. Pharmacol. 51, 1-10 (2020).

disease-associatedcardiacinflammation and fibrosis. Nat. Commun. 12,2783 (2021).
21. Daniel, C. B. et al. Signaling by vitamin A andretinol-binding

proteinregulates

gene

17. Xu, J. et al. GPR68 senses flow and is essential

expression to inhibit insulin responses. Proc.

for vascular physiology. Cell. 173, 762-775

Natl. Acad. Sci. U. S. A. 108, 4340-4345 (2011).

(2018).

22. Komarova, S. V. et al. Convergent signaling by

18. Sabatini, S. The acidosis of chronic renal failure.

acidosis and receptor activator of NF-kappaB

Med. Clin. North. Am. 67, 845-58 (1983).

ligand (RANKL) on the calcium / calcineurin /19. Mountokalakis, T. D. Magnesium metabolism

NFAT pathway in osteoclasts. Proc. Natl. Acad.

in chronic renal failure. Magnes. Res. 3, 121127 (1990).

᫬㛫⏕≀Ꮫ9RO1R 

Sci. U. S. A. 102, 2643-2648 (2005).