New therapeutic strategy for diabetic kidney disease by inhibiting MGAT

2020 Fiscal Year Research-status Report

• Project/Area Number: 20K21773
• Research Institution: Kanazawa Medical University
• Principal Investigator: 古家 大祐 金沢医科大学, 医学部, 教授 (70242980)
• Co-Investigator(Kenkyū-buntansha): 北田 宗弘 金沢医科大学, 医学部, 准教授 (40434469)
• Project Period (FY): 2020-07-30 – 2023-03-31
• Keywords: PKC / 糖尿病性腎臓病 / SGLT-２阻害薬 / MGAT2

Outline of Annual Research Achievements

我々はマウス系統間の腎障害相違に注目し、１型糖尿病モデルで汎用されるストレプトゾトシン(STZ)誘導糖尿病C57BL6マウスの腎障害程度は軽度であるが、STZ誘導糖尿病CD-1マウスが重度腎線維化を呈することと、その分子機構を解明してきた。そこで慢性高血糖暴露にてCD-1マウス自体が線維化を呈しやすい可能性を考慮し、db遺伝子を戻し交配にてCD-1に導入し顕著な腎線維化を有する2型糖尿病モデル動物CD-1db/dbを作成した。
腎遺伝子発現アレイ解析にて、異常解糖系遺伝子の変動が明らかとなり我々はCD1db/dbにおいてBKSdb/dbやCD1db/mに比し有意に増加している遺伝子群の中で、monoacylglycerol acyltransferase 2 (MGAT2)に注目した。
今年度は、CD1db/db腎にてDAG蓄積によりPKC・MAPK活性が増強されることも確認した。さらに、SGLT2阻害薬およびMGAT2阻害によりPKC活性化の抑制が糖尿病性腎臓病を改善するか否かをした。その結果、SGLT2阻害薬投与によってSTZ誘発1型糖尿病CD-1の腎臓におけるPKC活性化を抑制して、上皮-間葉化を介する腎線維を改善することを見出した。

Current Status of Research Progress

3: Progress in research has been slightly delayed.

Reason

SGLT-2阻害薬によって、STZ誘発1型糖尿病性腎臓病の線維化を、PKC活性の抑制を介して改善することは見いだせた。しかし、腎構成細胞のsingle cell解析とMFAT2阻害による糖尿病性腎臓病に対する効果に関する実験は未だ進捗中であり結果を見出せてない。

Strategy for Future Research Activity

MGAT2発現細胞の解明を、single cell解析にて行うとともに、MGAT2阻害薬の糖尿病性腎臓病に対する有効性を検討していく。

Research Products

• [Journal Article] Effect of Methionine Restriction on Aging: Its Relationship to Oxidative Stress. (2021)
  • Author(s): Kitada M, Ogura Y, Monno I, Xu J, Koya D.
  • Journal Title: Biomedicines. Volume: - Pages: -
  • DOI: 10.3390/biomedicines9020130.
  • Peer Reviewed / Open Access
• [Journal Article] Metformin Mitigates DPP-4 Inhibitor-Induced Breast Cancer Metastasis via Suppression of mTOR Signaling (2021)
  • Author(s): Kawakita E, Yang F, Kumagai A, Takagaki Y, Kitada M, Yoshitomi Y, Ikeda T, Nakamura Y, Ishigaki Y, Kanasaki K, Koya D.
  • Journal Title: Mol Cancer Res. Volume: - Pages: -
  • DOI: 10.1158/1541-7786.MCR-20-0115
  • Peer Reviewed / Open Access
• [Journal Article] Randomized trial of an intensified, multifactorial intervention in patients with advanced-stage diabetic kidney disease: Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT-Japan) (2021)
  • Author(s): Shikata K, Haneda M, Ninomiya T, Koya D, Suzuki Y, Suzuki D, Ishida H, Akai H, Tomino Y, Uzu T, Nishimura M, Maeda S, Ogawa D, Miyamoto S, Makino H; Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT-Japan) collaborative group.
  • Journal Title: J Diabetes Investig. Volume: 12 Pages: 207-216
  • DOI: 10.1111/jdi.13339.
  • Peer Reviewed
• [Journal Article] Loss of endothelial glucocorticoid receptor accelerates diabetic nephropathy. (2021)
  • Author(s): Srivastava SP, Zhou H, Setia O, Liu B, Kanasaki K, Koya D, Dardik A, Fernandez-Hernando C, Goodwin J.
  • Journal Title: Nat Commun. Volume: 12 Pages: 2368.
  • DOI: 10.1038/s41467-021-22617-y.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Anterior pituitary function in Rathke's cleft cysts versus nonfunctioning pituitary adenomas (2021)
  • Author(s): Fujii M, Nakagawa A, Tachibana O, Iizuka H, Koya D.
  • Journal Title: Endocr J. Volume: - Pages: -
  • DOI: 10.1507/endocrj.EJ21-0050.
  • Peer Reviewed / Open Access
• [Journal Article] Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes. (2020)
  • Author(s): Bakris GL, Agarwal R, Anker SD, Pitt B, Ruilope LM, Rossing P, Kolkhof P, Nowack C, Schloemer P, Joseph A, Filippatos G; FIDELIO-DKD Investigators.
  • Journal Title: N Engl J Med. Volume: 3893 Pages: 2219-2229.
  • DOI: 10.1056/NEJMoa2025845. Epub 2020 Oct 23.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Renal protective effects of empagliflozin via inhibition of EMT and aberrant glycolysis in proximal tubules (2020)
  • Author(s): Li J, Liu H, Takagi S, Nitta K, Kitada M, Srivastava SP, Takagaki Y, Kanasaki K, Koya D.
  • Journal Title: JCI Insight . Volume: 5 Pages: e129034.
  • DOI: 10.1172/jci.insight.129034.
  • Peer Reviewed
• [Journal Article] Endothelial autophagy deficiency induces IL6 - dependent endothelial mesenchymal transition and organ fibrosis (2020)
  • Author(s): Takagaki Y, Lee SM, Dongqing Z, Kitada M, Kanasaki K, Koya D.
  • Journal Title: Autophagy. Volume: 16 Pages: 1905-1914.
  • DOI: 10.1080/15548627.2020.1713641.
  • Peer Reviewed
• [Journal Article] The impact of mitochondrial quality control by Sirtuins on the treatment of type 2 diabetes and diabetic kidney disease (2020)
  • Author(s): Xu J, Kitada M, Koya D.
  • Journal Title: Biochim Biophys Acta Mol Basis Dis Volume: 1866 Pages: 165756.
  • DOI: 10.1016/j.bbadis.2020.165756.
  • Peer Reviewed / Open Access
• [Journal Article] CD38 inhibition by apigenin ameliorates mitochondrial oxidative stress through restoration of the intracellular NAD +/NADH ratio and Sirt3 activity in renal tubular cells in diabetic rats (2020)
  • Author(s): Ogura Y, Kitada M, Xu J, Monno I, Koya D.
  • Journal Title: Aging (Albany NY) . Volume: 12 Pages: 11325-11336.
  • DOI: 10.18632/aging.103410.
  • Peer Reviewed / Open Access
• [Journal Article] The PKM2 activator TEPP-46 suppresses kidney fibrosis via inhibition of the EMT program and aberrant glycolysis associated with suppression of HIF-1α accumulation (2020)
  • Author(s): Liu H, Takagaki Y, Kumagai A, Kanasaki K, Koya D.
  • Journal Title: J Diabetes Investig. Volume: - Pages: -
  • DOI: 10.1111/jdi.13478.
  • Peer Reviewed / Open Access
• [Journal Article] Manganese Superoxide Dismutase Dysfunction and the Pathogenesis of Kidney Disease (2020)
  • Author(s): Kitada M, Xu J, Ogura Y, Monno I, Koya D.
  • Journal Title: Front Physiol . Volume: 11 Pages: 755.
  • DOI: 10.3389/fphys.2020.00755.
  • Peer Reviewed / Open Access
• [Journal Article] Mechanism of Activation of Mechanistic Target of Rapamycin Complex 1 by Methionine (2020)
  • Author(s): Kitada M, Xu J, Ogura Y, Monno I, Koya D.
  • Journal Title: Front Cell Dev Biol . Volume: 8 Pages: 715.
  • DOI: 10.3389/fcell.2020.00715.
  • Peer Reviewed / Open Access
• [Journal Article] Recent Insights Into SREBP as a Direct Mediator of Kidney Fibrosis via Lipid-Independent Pathways (2020)
  • Author(s): Dorotea D, Koya D, Ha H.
  • Journal Title: Front Pharmacol . Volume: 11 Pages: 265.
  • DOI: 10.3389/fphar.2020.00265.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Metabolic reprogramming by N-acetyl-seryl-aspartyl-lysyl-proline protects against diabetic kidney disease (2020)
  • Author(s): Srivastava SP, Goodwin JE, Kanasaki K, Koya D.
  • Journal Title: Br J Pharmacol. Volume: 177 Pages: 3691-3711.
  • DOI: 10.1111/bph.15087
  • Peer Reviewed
• [Journal Article] Significance of SGLT2 inhibitors: lessons from renal clinical outcomes in patients with type 2 diabetes and basic researches (2020)
  • Author(s): Kitada M, Hirai T, Koya D.
  • Journal Title: Diabetol Int. Volume: 11 Pages: 245-251.
  • DOI: 10.1007/s13340-020-00444-8.
  • Peer Reviewed
• [Journal Article] Medical nutrition therapy and dietary counseling for patients with diabetes-energy, carbohydrates, protein intake and dietary counseling (2020)
  • Author(s): Yamauchi T, Kamiya H, Utsunomiya K, Watada H, Kawanami D, Sato J, Kitada M, Koya D, Harada N, Shide K, Joo E, Suzuki R, Bouchi R, Ohta Y, Kondo T.
  • Journal Title: Diabetol Int. Volume: 11 Pages: 224-239.
  • DOI: 10.1007/s13340-020-00437-7.
  • Peer Reviewed
• [Journal Article] Inhibition of Angiotensin-Converting Enzyme Ameliorates Renal Fibrosis by Mitigating DPP-4 Level and Restoring Antifibrotic MicroRNAs (2020)
  • Author(s): Srivastava SP, Goodwin JE, Kanasaki K, Koya D.
  • Journal Title: Genes (Basel) . Volume: 11 Pages: 211.
  • DOI: 10.3390/genes11020211.
  • Peer Reviewed / Open Access
• [Journal Article] CD-1 db/db mice: A novel type 2 diabetic mouse model with progressive kidney fibrosis (2020)
  • Author(s): Mizunuma Y, Kanasaki K, Nitta K, Nakamura Y, Ishigaki Y, Takagaki Y, Kitada M, Li S, Liu H, Li J, Usui I, Aso Y, Koya D.
  • Journal Title: J Diabetes Investig . Volume: 11 Pages: 1470-1481.
  • DOI: 10.1111/jdi.13311.
  • Peer Reviewed / Open Access
• [Journal Article] Deficiency in Dipeptidyl Peptidase-4 Promotes Chemoresistance through the CXCL12/CXCR4/mTOR/TGFβ Signaling Pathway in Breast Cancer Cells (2020)
  • Author(s): Li S, Fan Y, Kumagai A, Kawakita E, Kitada M, Kanasaki K, Koya D.
  • Journal Title: Int J Mol Sci. Volume: 21 Pages: 805.
  • DOI: 10.3390/ijms21030805.
  • Peer Reviewed / Open Access
• [Journal Article] Pro-inflammatory macrophages coupled with glycolysis remodel adipose vasculature by producing platelet-derived growth factor-B in obesity (2020)
  • Author(s): Onogi Y, Wada T, Okekawa A, Matsuzawa T, Watanabe E, Ikeda K, Nakano M, Kitada M, Koya D, Tsuneki H, Sasaoka T.
  • Journal Title: Sci Rep . Volume: 10 Pages: 670.
  • DOI: 10.1038/s41598-019-57368-w.
  • Peer Reviewed / Open Access
• [Journal Article] Supplementation with Red Wine Extract Increases Insulin Sensitivity and Peripheral Blood Mononuclear Sirt1 Expression in Nondiabetic Humans (2020)
  • Author(s): Kitada M, Ogura Y, Monno I, Koya D.
  • Journal Title: Nutrients . Volume: 12 Pages: 3108.
  • DOI: 10.3390/nu12103108.
  • Peer Reviewed / Open Access
• [Journal Article] Endothelial FGFR1 (Fibroblast Growth Factor Receptor 1) Deficiency Contributes Differential Fibrogenic Effects in Kidney and Heart of Diabetic Mice (2020)
  • Author(s): Li J, Liu H, Srivastava SP, Hu Q, Gao R, Li S, Kitada M, Wu G, Koya D, Kanasaki K.
  • Journal Title: Hypertension . Volume: 76 Pages: 1935-1944.
  • DOI: 10.1161/HYPERTENSIONAHA.120.15587.
  • Peer Reviewed
• [Journal Article] Methionine abrogates the renoprotective effect of a low-protein diet against diabetic kidney disease in obese rats with type 2 diabetes (2020)
  • Author(s): Kitada M, Ogura Y, Monno I, Xu J, Koya D.
  • Journal Title: Aging (Albany NY) . Volume: 12 Pages: 4489-4505.
  • DOI: 10.18632/aging.102902.
  • Peer Reviewed / Open Access
• [Journal Article] Stromal cell-derived factor 1 (SDF1) attenuates platelet-derived growth factor-B (PDGF-B)-induced vascular remodeling for adipose tissue expansion in obesity (2020)
  • Author(s): Watanabe E, Wada T, Okekawa A, Kitamura F, Komatsu G, Onogi Y, Yamamoto S, Sasahara M, Kitada M, Koya D, Tsuneki H, Sasaoka T.
  • Journal Title: Angiogenesis . Volume: 23 Pages: 667-684.
  • DOI: 10.1007/s10456-020-09738-6.
  • Peer Reviewed
• [Journal Article] Prevalence of albuminuria and renal dysfunction, and related clinical factors in Japanese patients with diabetes: The Japan Diabetes Complication and its Prevention prospective study 5 (2020)
  • Author(s): Shikata K, Kodera R, Utsunomiya K, Koya D, Nishimura R, Miyamoto S, Tajima N; JDCP study group.
  • Journal Title: J Diabetes Investig . Volume: 11 Pages: 325-332.
  • DOI: 10.1111/jdi.13116.
  • Peer Reviewed / Open Access
• [Journal Article] Case report of superior mesenteric artery syndrome that developed in a lean type 2 diabetes patient and was associated with rapid body weight loss after sodium-glucose cotransporter 2 inhibitor administration (2020)
  • Author(s): Hirai T, Kitada M, Hayashi Y, Monno I, Takagaki Y, Shimada K, Ogura Y, Fujii M, Konishi K, Nakagawa A, Koya D.
  • Journal Title: J Diabetes Investig . Volume: 11 Pages: 1359-1362.
  • DOI: 10.1111/jdi.13228.
  • Peer Reviewed / Open Access
• [Remarks] 金沢医科大学 糖尿病・内分泌内科学
  • URL: http://www.kanazawa-med.ac.jp/~endocrin/