New therapeutic strategy for diabetic nephropathy via autophagy regulation

• Project/Area Number: 25670414
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Kidney internal medicine
• Research Institution: Kanazawa Medical University
• Principal Investigator: KOYA Daisuke 金沢医科大学, 医学部, 教授 (70242980)
• Co-Investigator(Kenkyū-buntansha): KANASAKI Keizo 金沢医科大学, 医学部, 准教授 (60589919) ; KANASAKI Megumi 金沢医科大学, 医学部, 助教 (50599355)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2015: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: オートファジー / 糖尿病 / 内皮・間葉転化 / microRNA / 内皮細胞 / IL-6 / AcSDKP / 腎線維化 / miRNA / 糖尿病腎症 / マイクロRNA / メトフォルミン

Outline of Final Research Achievements

Renal fibrosis in diabetic mouse model was ameliorated by inhibition of endothelial-mesenchymal conversion via the anti-fibrotic microRNA29 and let-7 induction with an endogenous anti-fibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) administration. In addition, although renal fibrosis has been caused by the enhancement of the DPP-4 expression by reduced microRNA29 expression in diabetic state, it has improved by microRNA29 expression with a DPP-4 inhibitor, linagliptin administration.

Research Products

• [Journal Article] Oral Administration of N-Acetyl-seryl-aspartyl-lysyl-proline Ameliorates Kidney Disease in Both Type 1 and Type 2 Diabetic Mice via a Therapeutic Regimen (2016)
  • Author(s): Nitta K, Shi S, Nagai T, Kanasaki M, Kitada M, Srivastava SP, Haneda M, Kanasaki K, Koya D.
  • Journal Title: Biomed Res Int Volume: 2016:9172157 Pages: 9172157-9172157
  • DOI: 10.1155/2016/9172157
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A very-low-protein diet ameliorates advanced diabetic nephropathy through autophagy induction by suppression of the mTORC1 pathway in Wistar fatty rats, an animal model of type 2 diabetes and obesity. (2016)
  • Author(s): Kitada M, Ogura Y, Suzuki T, Sen S, Lee SM, Kanasaki K, Kume S, Koya D.
  • Journal Title: Diabetologia Volume: in press Issue: 6 Pages: 1307-17
  • DOI: 10.1007/s00125-016-3925-4
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Dipeptidyl peptidase-4 and kidney fibrosis in diabetes. (2016)
  • Author(s): Shi S, Koya D, Kanasaki K.
  • Journal Title: Fibrogenesis Tissue Repair Volume: 9 Issue: 1 Pages: 1-10
  • DOI: 10.1186/s13069-016-0038-0
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Linagliptin but not Sitagliptin inhibited transforming growth factor-β2-induced endothelial DPP-4 activity and the endothelial-mesenchymal transition (2016)
  • Author(s): Shi S, Kanasaki K, Koya D
  • Journal Title: Biochem Biophys Res Commun Volume: 26 Issue: 1 Pages: 184-190
  • DOI: 10.1016/j.bbrc.2016.01.154
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Interactions of DPP-4 and integrin β1 influences endothelial-to mesenchymal transition. (2015)
  • Author(s): Shi S, Srivastava SP, Kanasaki M, He J, Kitada M, Nagai T, Nitta K, Takagi S, Kanasaki K, Koya D.
  • Journal Title: Kidney Int. Volume: - Issue: 3 Pages: 479-489
  • DOI: 10.1038/ki.2015.103
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The biological significance of angiotensisn-converting enzyme inhibition to combat kidney fibrosis (2015)
  • Author(s): Nagai T, Nitta K, Kanasaki M, Koya D, Kanasaki K.
  • Journal Title: Clin Exp Nephrol. Volume: 19 Issue: 1 Pages: 65-74
  • DOI: 10.1007/s10157-014-1000-3
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] N-acetyl-seryl-aspartyl-lysyl-proline inhibits diabetes-associated kidney fibrosis and endothelial-mesenchymal transition (2014)
  • Author(s): Takako Nagai, Megumi Kanasaki, Swayam Prakash Srivastava, Yuka Nakamura, Yasuhito Ishigaki, Munehiro Kitada, Sen Shi, Keizo Kanasaki, Daisuke Koya
  • Journal Title: BioMed Research International Volume: 2014 Pages: 696475-696475
  • DOI: 10.1155/2014/696475
  • Peer Reviewed / Open Access
• [Journal Article] N-acetyl-seryl-aspartyl-lysyl-proline: a valuable endogenous anti-fibrotic peptide for combating kidney fibrosis in diabetes. (2014)
  • Author(s): Kanasaki K, Nagai T, Nitta K, Kitada M, Koya D.
  • Journal Title: Front Pharmacol. Volume: 2014 Pages: 1-11
  • DOI: 10.3389/fphar.2014.00070
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Linagriptin-mediated DPP-4 inhibition ameliorates kidney fibrosis in streptozotocin-induced diabeticmice by inhibiting endothelial-to mesenchymal transition in a therapeutic regimen. (2014)
  • Author(s): Kanasaki K, Shi S, Kanasaki M, He J, Nagai T, Nakamura Y, Ishigaki Y, Kitada M, Srivastava SP, Koya D.
  • Journal Title: Diabetes. Volume: 63 Issue: 6 Pages: 2120-2131
  • DOI: 10.2337/db13-1029
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Fatty acids are novel nutrient factors to regulate mTORC1 lysosomal localization and apoptosis in podocytes. (2014)
  • Author(s): Yasuda M, Tanaka Y, Kume S, Morita Y, Chin-Kanasaki M, Araki H, Isshiki K, Araki SI, Koya D, Haneda M, Kashiwagi A, Maegawa H, Uzu T.
  • Journal Title: Biochim Biophys Acta. Volume: 1842 Issue: 7 Pages: 1097-1108
  • DOI: 10.1016/j.bbadis.2014.04.001
  • Peer Reviewed / Open Access
• [Journal Article] Autophagy: emerging therapeutic target for diabetic nephropathy. (2014)
  • Author(s): Kume S, Yamahara K, Yasuda M, Maegawa H, Koya D.
  • Journal Title: Semin Nephrol. Volume: 34 Issue: 1 Pages: 9-16
  • DOI: 10.1016/j.semnephrol.2013.11.003
  • Peer Reviewed
• [Journal Article] Role of sirtuins in kidney disease. (2014)
  • Author(s): Kitada M, Kume S, Koya D.
  • Journal Title: Curr Opin Nephrol Hypertens. Volume: 23 Issue: 1 Pages: 75-79
  • DOI: 10.1097/01.mnh.0000437330.85675.ac
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Interventions against nutrient-sensing pathways represent an emerging new therapeutic approach for diabetic nephropathy (2013)
  • Author(s): Koya D, Kitada M, Kume S, Kanasaki K
  • Journal Title: Clin Exp Nephrol Volume: 18(2) Issue: 2 Pages: 210-213
  • DOI: 10.1007/s10157-013-0908-3
  • Peer Reviewed
• [Journal Article] Eplerenone ameliorates the phenotypes of metabolic syndrome with NASH in liver-specific SREBP1c Tg mice fed high-fat and high-fructose diet (2013)
  • Author(s): Wada T, Miyashita Y, Sasaki M, Aruga Y, Nakamura Y, Ishii Y, Sasahara M, Kanasaki K, Kitada M, Koya D, Shimano H, Tsuneki H, Sasaoka
  • Journal Title: Am J Physiol Endocrinol Metab Volume: 305 Issue: 11 Pages: E1415-E1425
  • DOI: 10.1152/ajpendo.00419.2013
  • Peer Reviewed
• [Journal Article] The use of calorie restriction mimetics to study aging. (2013)
  • Author(s): Kitada M, Koya D.
  • Journal Title: Methods Mol Biol. Volume: 1048 Pages: 95-107
  • DOI: 10.1007/978-1-62703-556-9_8
  • ISBN: 9781627035552, 9781627035569
  • Peer Reviewed
• [Journal Article] Altered unfolded protein response is implicated in the age-related exacerbation of proteinuria-induced proximal tubular cell damage. (2013)
  • Author(s): Takeda N, Kume S, Tanaka Y, Morita Y, Chin-Kanasaki M, Araki H, Isshiki K, Araki S, Haneda M, Koya D, Kashiwagi A, Maegawa H, Uzu T.
  • Journal Title: Am J Pathol. Volume: 183 Issue: 3 Pages: 774-85
  • DOI: 10.1016/j.ajpath.2013.05.026
  • Peer Reviewed
• [Journal Article] Cilostazol attenuates spontaneous microaggregation of platelets in type 2 diabetic patients with insufficient platelet response to aspirin. (2013)
  • Author(s): Araki S, Matsuno H, Haneda M, Koya D, Kanno Y, Kume S, Isshiki K, Araki H, Ugi S, Kawai H, Kashiwagi A, Uzu T, Maegawa H.
  • Journal Title: Diabetes Care Volume: 36(7) Issue: 7 Pages: e92-e93
  • DOI: 10.2337/dc12-2702
  • Peer Reviewed
• [Journal Article] Calorie restriction in overweight males ameliorates obesity-related metabolic alterations and cellular adaptations through anti-aging effects, possibly including AMPK and SIRT1 activation. (2013)
  • Author(s): Kitada M, Kume S, Takeda-Watanabe A, Tsuda S, Kanasaki K, Koya D.
  • Journal Title: Biochim Biophys Acta Volume: 1830(10) Issue: 10 Pages: 4820-4827
  • DOI: 10.1016/j.bbagen.2013.06.014
  • Peer Reviewed
• [Journal Article] Ketogenic essential amino acids replacement diet ameliorated hepatosteatosis with altering autophagy-associated molecules. (2013)
  • Author(s): Xu L, Kanasaki M, He J, Kitada M, Nagao K, Jinzu H, Noguchi Y, Maegawa H, Kanasaki K, Koya D.
  • Journal Title: Biochim Biophys Acta. Volume: 1832(10) Issue: 10 Pages: 1605-1612
  • DOI: 10.1016/j.bbadis.2013.05.003
  • Peer Reviewed
• [Journal Article] Statin use in patients with diabetes and kidney disease: the Japanese experience. (2013)
  • Author(s): Koya D, Campese VM.
  • Journal Title: J Atheroscler Thromb. Volume: 20 Pages: 407-424
  • NAID: 130004444686
  • Peer Reviewed
• [Journal Article] Role of the Endothelial-to-mesenchymal Transition in Renal Fibrosis of Chronic Kidney Disease (2013)
  • Author(s): Jianhua He, Yong Xu, Daisuke Koya, Keizo Kanasaki
  • Journal Title: 2013 Clin Exp Nephrol Clin Exp Nephrol Volume: 17(4) Issue: 4 Pages: 488-497
  • DOI: 10.1007/s10157-013-0781-0
  • NAID: 10031195312
  • Peer Reviewed
• [Journal Article] Predictive effects of urinary liver-type fatty acid-binding protein for deteriorating renal function and incidence of cardiovascular disease in type 2 diabetic patients without advanced nephropathy. (2013)
  • Author(s): Araki S, Haneda M, Koya D, Sugaya T, Isshiki K, Kume S, Kashiwagi A, Uzu T, Maegawa H.
  • Journal Title: Diabetes Care. Volume: 36 Issue: 5 Pages: 1248-1253
  • DOI: 10.2337/dc12-1298
  • Peer Reviewed
• [Journal Article] Sirtuins and renal diseases: relationship with aging and diabetic nephropathy (2013)
  • Author(s): Kitada M.
  • Journal Title: Clin Sci (Lond) Volume: 124(3) Issue: 3 Pages: 153-64
  • DOI: 10.1042/cs20120190
  • Peer Reviewed
• [Remarks] 金沢医科大学 糖尿病・内分泌内科
  • URL: http://www.kanazawa-med.ac.jp/~endocrin/
• [Remarks] 金沢医科大学 糖尿病・内分泌内科学
  • URL: http://www.kanazawa-med.ac.jp/~endocrin/