Study on the mechanisms of kidney disease progression and their regulation: roles of chronic inflammation and humoral mediators
Project/Area Number |
20K08611
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 53040:Nephrology-related
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Research Institution | Kumamoto University |
Principal Investigator |
MUKOYAMA Masashi 熊本大学, 大学院生命科学研究部(医), 教授 (40270558)
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Project Period (FY) |
2020-04-01 – 2023-03-31
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Project Status |
Completed (Fiscal Year 2022)
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Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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Keywords | 慢性腎臓病 / 慢性炎症 / 糖尿病性腎症 / マクロファージ / ERストレス / MRP8 / ANGPTL2 / オステオクリン / エクソソーム / シングルセル解析 / 急性腎障害 / osteocrin / バイオマーカー / 慢性腎躁病 / 臓器連関 |
Outline of Research at the Start |
これまでCKDの治療を目標として数多くの研究がなされてきたが、いまだ進行を抑止するのに十分な治療法は開発されていない。本研究は、腎障害進展に重要と考えられる腎内慢性炎症に着目し、さらにそれを司る液性因子に焦点をあてながら、それらによる病態解明と新たな治療応用を目指して研究を進めていく。特に、マクロファージに由来する炎症惹起因子MRP8、また腎臓で多くの細胞が産生し多彩な機能を有するANGPTL2は炎症持続の重要な分子基盤となっている可能性が高く、その機序の解明及びこれらを標的とした創薬を目指して研究を行う。さらに、骨由来で腎臓でも産生されるOstnの腎保護作用についても明らかにする。
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Outline of Final Research Achievements |
Chronic kidney disease (CKD) is a growing health problem worldwide. The mechanisms for CKD progression remain obscure, and therefore we explored key factors, focusing on chronic inflammation and humoral factors. We found that a macrophage-derived factor MRP8 is critical in disease progression through intra-glomerular crosstalk, activated by mesangium-derived exosomes. Mesangium-derived factors also impair podocyte function in diabetes through inhibition of ER-associated degradation. We found several factors that may aggravate CKD with diabetes by single-cell RNA analysis. A potential proinflammatory factor ANGPTL2, in contrast, may work renoprotective in an ischemia-reperfusion injury (IRI) model. In addition, bone-derived osteocrin can exert renoprotective actions upon IRI by potentiating natriuretic peptide actions locally. Furthermore, high serum levels of MRP8 and ANGPTL2 can be risk factors in hemodialysis patients. These findings may provide potential therapeutic targets for CKD.
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Academic Significance and Societal Importance of the Research Achievements |
糖尿病性腎症に代表されるmetabolic kidney diseaseにおける局所因子の意義、特にマクロファージ由来炎症惹起因子の増悪因子としての役割を明らかにすることで、これらを標的とした新たな創薬への基盤となる。さらに、急性腎障害慢性化の機序を明らかにすることで腎症進展阻止のための治療戦略となりうる。MRP8やANGPLT2、オステオクリンはその候補分子であり、これらを標的とした治療法はなく、病態での意義の解析から新たな治療戦略の提案へと繋がる可能性がある。一方で、これらの血中濃度は腎症患者の予後予測におけるバイオマーカーとしての意義が示唆され、今後の腎疾患診療に貢献する可能性が高い。
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Report
(4 results)
Research Products
(56 results)
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[Journal Article] Effects of Roxadustat on Erythropoietin Production in the Rat Body2022
Author(s)
Yasuoka Yukiko,Izumi Yuichiro,Fukuyama Takashi,Omiya Haruki,Pham Truyen D.,Inoue Hideki,Oshima Tomomi,Yamazaki Taiga,Uematsu Takayuki,Kobayashi Noritada,Shimada Yoshitaka,Nagaba Yasushi,Yamashita Tetsuro,Mukoyama Masashi,Sato Yuichi,Wall Susan M.,Sands Jeff M.,Takahashi Noriko,Kawahara Katsumasa,Nonoguchi Hiroshi
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Journal Title
Molecules
Volume: 27
Issue: 3
Pages: 1119-1119
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Regulation of Rhcg, an ammonia transporter, by aldosterone in the kidney.2021
Author(s)
Eguchi K, Izumi Y, Yasuoka Y, Nakagawa T, Ono M, Maruyama K, Matsuo N, Hiramatsu A, Inoue H, Nakayama Y, Nonoguchi H, Lee HW, Weiner ID, Kakizoe Y, Kuwabara T, Mukoyama M.
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Journal Title
J Endocrinol.
Volume: in press
Issue: 2
Pages: 95-112
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Circulating angiopoietin-like protein 2 levels and arterial stiffness in patients receiving maintenance hemodialysis: A cross-sectional study.2020
Author(s)
Fukami H, Morinaga J, Okadome Y, Nishiguchi Y, Iwata Y, Kanki T, Nakagawa T, Izumi Y, Kakizoe Y, Kuwabara T, Horiguchi H, Sato M, Kadomatsu T, Miyata K, Tajiri T, Oike Y, Mukoyama M.
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Journal Title
Atherosclerosis.
Volume: 315
Pages: 18-23
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Differentiation of endogenous erythropoietin and exogenous ESAs by Western blotting.2020
Author(s)
Yasuoka Y, Fukuyama T, Izumi Y, Yamashita T, Nakayama Y, Inoue H, Yanagita K, Oshima T, Yamazaki T, Uematsu T, Kobayashi N, Shimada Y, Nagaba Y, Mukoyama M, Sato Y, Sands JM, Kawahara K, Nonoguchi H.
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Journal Title
Heliyon.
Volume: 6
Issue: 11
Pages: e05389-e05389
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Suppressed ER-associated degradation by intraglomerular cross talk between mesangial cells and podocytes causes podocyte injury in diabetic kidney disease.2020
Author(s)
Fujimoto D, Kuwabara T, Hata Y, Umemoto S, Kanki T, Nishiguchi Y, Mizumoto T, Hayata M, Kakizoe Y, Izumi Y, Takahashi S, Mukoyama M.
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Journal Title
FASEB J
Volume: 34
Issue: 11
Pages: 854-860
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Erythropoietin production by the kidney and the liver in response to severe hypoxia evaluated by Western blotting with deglycosylation2020
Author(s)
Yukiko Yasuoka, Takashi Fukuyama, Yuichiro Izumi, Yushi Nakayama, Hideki Inoue, Kengo Yanagita, Tomomi Oshima, Taiga Yamazaki, Takayuki Uematsu 2, Noritada Kobayashi 2, Yoshitaka Shimada 5, Yasushi Nagaba, Masashi Mukoyama, Tetsuro Yamashita, Yuichi Sato, Jeff M Sands, Katsumasa Kawahara, Hiroshi Nonoguchi
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Journal Title
Physiol Rep.
Volume: 12
Issue: 12
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Pivotal role of podocyte autophagy against glomerular endothelial dysfunction in diabetes.2020
Author(s)
Yoshibayashi M, Kume S, Yasuda-Yamahara M, Yamahara K, Takeda N, Osawa N, Chin-Kanasaki M, Nakae Y, Yokoi H, Mukoyama M, Asanuma K, Maegawa H, Araki SI.
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Journal Title
Biochem Biophys Res Commun.
Volume: 525
Issue: 2
Pages: 319-325
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Circulating angiopoietin-like protein 2 levels and mortality risk in patients receiving maintenance hemodialysis: a prospective cohort study2019
Author(s)
Morinaga J, Kakuma T, Fukami H, Hayata M, Uchimura K, Mizumoto T, Kakizoe Y, Miyoshi T, Shiraishi N, Adachi M, Izumi Y, Kuwabara T, Okadome Y, Sato M, Horiguchi H, Sugizaki T, Kadomatsu T, Miyata K, Tajiri S, Tajiri T, Tomita K, Kitamura K, Oike Y, Mukoyama M.
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Journal Title
Nephrology Dialysis Transplantation
Volume: 印刷中
Issue: 5
Pages: 854-860
DOI
Related Report
Peer Reviewed / Open Access
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