The significance of Klotho in bone and mineral metabolism disorders in diabetes

• Project/Area Number: 22590895
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Nara Medical University
• Principal Investigator: NAKATANI Kimihiko 奈良県立医科大学, 医学部, 学内講師 (80398445)
• Co-Investigator(Kenkyū-buntansha): SAITO Yoshihiko 奈良県立医科大学, 医学部, 教授 (30250260)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2012: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2011: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2010: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: α-Klotho / 糖尿病性腎症 / 尿中カルシウム排泄 / 骨代謝マーカー / α－Klotho / TRPV5 / 分泌型α-Klotho / 膜型α-Klotho / FGF23 / 腎臓病

Research Abstract

Renal α-Klotho expression was significantly lower and urinary calcium excretion significantly higher in diabetic nephropathy than in IgA nephropathy with an eGFR greater than 60 ml/min per 1.73m2 . Multiple regression analyses indicated that α-Klotho mRNA was inversely correlated with calcium excretion. We also confirmed a reduction of renal α-Klotho mRNA down to almost 50% and enhanced calcium excretion in mice with STZ-induced diabetic nephropathy in comparison with nondiabetic mice. Hypercalciuria was exacerbated in heterozygous α-Klotho knockout mice in comparison with wild-type mice, each with STZ-induced diabetic nephropathy. Thus, α-Klotho expression was decreased in distal convoluted tubules in diabetic nephropathy in humans and mice. Renal loss of α-Klotho may affect urinary calcium excretion in early diabetic nephropathy. However, we cannot confirm the direct associations of renal α-Klotho deficiency with bone metabolism abnormalities in diabetic nephropathy.

Research Products

• [Journal Article] Decreased renal α-Klotho expression in early diabetic nephropathy in humans and mice and its possible role in urinary calcium excretion (2012)
  • Author(s): Asai O, Nakatani K, Tanaka T, Sakan H, Imura A, Yoshimoto S, Samejima K, Yamaguchi Y, Matsui M, Akai Y, Konishi N, Iwano M, Nabeshima Y, Saito Y
  • Journal Title: Kidney Int Volume: 81(6) Pages: 539-47
  • Peer Reviewed
• [Journal Article] Clinical significance of fibroblast-specific protein-1 expression on podocytes in patients with focal segmental glomerulosclerosis (2012)
  • Author(s): Samejima K, Nakatani K, Suzuki D, Asai O, Sakan H, Yoshimoto S, Yamaguchi Y, Matsui M, Akai Y, Toyoda M, Iwano M, Saito Y
  • Journal Title: Nephron Clin Pract Volume: 120(1) Pages: 1-7
  • Peer Reviewed
• [Journal Article] Urinary FSP1 is a biomarker of crescentic GN (2012)
  • Author(s): Iwano M, Yamaguchi Y, Iwamoto T, Nakatani K, Matsui M, Kubo A, Akai Y, Mori T, Saito Y
  • Journal Title: J Am Soc Nephrol Volume: 23(2) Pages: 209-14
  • Peer Reviewed
• [Journal Article] A new drug delivery system for intravenous coronary thrombolysis with thrombus -targeting and stealth activity recoverable by ultrasound (2012)
  • Author(s): Kawata H, Uesugi Y, Soeda T, Takemoto Y, Sung JH, Umaki K, Kato K, Ogiwara K, Nogami K, Ishigami K, Horii M, Uemura S, Shima M, Tabata Y, Saito Y
  • Journal Title: J Am Coll Cardiol Volume: 60(24) Pages: 2550-2557
  • Peer Reviewed
• [Journal Article] Tmem100, an ALK1 receptor signaling-dependent gene essential for arterial endothelium differentiation and vascular morphogenesis (2012)
  • Author(s): Somekawa S, Imagawa K, Hayashi H, Sakabe M, Ioka T, Sato GE, Inada K, Iwamoto T, Mori T, Uemura S, Nakagawa O, Saito Y
  • Journal Title: PNAS Volume: 109(30) Pages: 12064-12069
  • Peer Reviewed
• [Journal Article] Decreased renalα-Klotho expression in early diabetic nephropathy in humans and mice and its possible role in urinary calcium excretion (2012)
  • Author(s): Asai O, Nakatani K, Tanaka T, Sakan H, Imura A, Yoshimoto S, Samejima K, Yamaguchi Y, Matsui M, Akai Y, Konishi N, Iwano M, Nabeshima Y, Saito Y
  • Journal Title: Kidney Int Volume: 81(6) Issue: 6 Pages: 539-47
  • DOI: 10.1038/ki.2011.423
  • Peer Reviewed
• [Journal Article] Urinary FSP1 is a biomarker of crescentic GN (2012)
  • Author(s): Iwano M, Nakatani K, et.al.
  • Journal Title: J Am Soc Nephrol Volume: 23 Pages: 209-214
  • Peer Reviewed
• [Journal Article] Low-dose Aspirin Therapy in Patients With Type 2 Diabetes Mellitus and Reduced Glomerular Filtration Rate: Subanalysis from the JPAD Trial (2011)
  • Author(s): Saito Y, Morimoto T, Ogawa H, Nakayama M, Uemura S, Doi N, Jinnouchi H, Waki M, Soejima H, Sugiyama S, Okada S, Akai Y
  • Journal Title: Diabetes Care Volume: 34(2) Pages: 280-285
  • Peer Reviewed
• [Journal Article] Macrophage Skewing by PHD2 Haplodeficiency Prevents Ischemia by Inducing Arteriogenesis (2011)
  • Author(s): Takeda Y, Costa S, Delamarre E, Roncal C, Leite de Oliveira R, Squadrito ML, Finisguerra V, Deschoemaeker S, Bruyere F, Wenes M, Hamm A, Serneels J, Magat J, Bhattacharyya T, Anisimov A, Jordan BF, Alitalo K, Maxwell P, Gallez B, Zhuang ZW, Saito Y, Simons M, De Palma M, Mazzone M.
  • Journal Title: Nature Volume: 479(7371) Pages: 122-126
  • Peer Reviewed
• [Journal Article] Clinical significance of fibroblast-specific protein-1 expression on podocytes in patients with focal segmental glomerulosclerosis (2011)
  • Author(s): Samejima K, Nakatani K, et.al.
  • Journal Title: Nephron Clin Pract Volume: 120
  • Peer Reviewed
• [Journal Article] Fractalkine expression and CD16+ monocyte accumulation in glomerular lesions: association with their severity and diversity in lupus models (2010)
  • Author(s): Nakatani K, Yoshimoto S, Iwano M, Asai O, Samejima K, Sakan H, Terada M, Hasegawa H, Nose M, Saito Y
  • Journal Title: Am J Physiol Renal Physiol Volume: 299(1) Pages: 207-16
  • Peer Reviewed
• [Journal Article] Establishment of sandwich ELISA for soluble alpha-Klotho measurement: Age-dependent change of soluble alpha-Klotho levels in healthy subjects (2010)
  • Author(s): Yamazaki Y, Imura A, Urakawa I, Shimada T, Murakami J, Aono Y, Hasegawa H, Yamashita T, Nakatani K, Saito Y, Okamoto N, Kurumatani N, Namba N, Kitaoka T, Ozono K, Sakai T, Hataya H, Ichikawa S, Imel EA, Econs MJ, Nabeshima
  • Journal Title: Biochem Biophys Res Commun Volume: 398(3) Pages: 513-518
  • Peer Reviewed
• [Journal Article] Establishment of sandwich ELISA for soluble alpha-Klotho measurement : Age-dependent change of soluble alpha-Klotho levels in healthy subjects. (2010)
  • Author(s): Yamazaki Y, Nakatani K, et al.
  • Journal Title: Biochem Biophys Res Commun. Volume: 398 Pages: 513-518
  • Peer Reviewed
• [Journal Article] Fractalkine expression and CD16+ monocyte accumulation in glomerular lesions : association with their severity and diversity in lupus models. (2010)
  • Author(s): Nakatani K, et al.
  • Journal Title: Am J Physiol Renal Physiol. Volume: 290 Pages: 207-216
  • Peer Reviewed
• [Presentation] 早期糖尿病性腎症での尿中カルシウム排泄増加にα-Klotho 発現低下を介した TRPV5 活性の低下が関与する (2012)
  • Author(s): 中谷公彦, 他
  • Organizer: 第55回日本腎臓学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2012-06-01
• [Presentation] 早期糖尿病性腎症での尿中カルシウム排泄増加にα-Klotho発現低下を介したTRPV5活性の低下が関与する． (2012)
  • Author(s): 中谷公彦 ら
  • Organizer: 第55回日本腎臓学会学術総会
  • Place of Presentation: 横浜
• [Presentation] 結節病変を有した糖尿病性腎症例における腎予後と臨床および病理組織学的指標との関連性 (2012)
  • Author(s): 森本勝彦，中谷公彦 ら
  • Organizer: 第55回日本腎臓学会学術総会
  • Place of Presentation: 横浜
• [Presentation] 慢性腎臓病症例と透析症例での血中α-Klotho濃度の検討 (2012)
  • Author(s): 浅井 修，中谷公彦 ら
  • Organizer: 第57回日本透析医学会
  • Place of Presentation: 札幌
• [Presentation] 糸球体内Fibroblast-specific protein1（FSP1）陽性細胞数および尿中FSP1量は (2012)
  • Author(s): 中谷公彦 ら
  • Organizer: 第56回日本リウマチ学会総会
  • Place of Presentation: 東京
• [Presentation] 可溶型E-selectin蛋白はMRL/1prマウスでの腎細動脈周囲のCD8陽性細胞浸潤と腎血管炎病変の進行を抑制した (2011)
  • Author(s): 吉本宗平, 中谷公彦, ら
  • Organizer: 日本腎臓学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2011-06-16
• [Presentation] 半月体病変判定における尿中FSP1の臨床的意義 (2011)
  • Author(s): 岩野正之, 中谷公彦, ら
  • Organizer: 日本腎臓学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2011-06-16
• [Presentation] 3年間腎機能が低下しないCKDステージ4,5症例の検討(予後判定における血尿の意義) (2011)
  • Author(s): 松井勝, 中谷公彦, ら
  • Organizer: 日本腎臓学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2011-06-16
• [Presentation] 慢性腎臓病(CKD)例での血中α-Klotho(sα-KL)濃度の検討 (2011)
  • Author(s): 左官弘和、中谷公彦, 他
  • Organizer: 第54回日本腎臓学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2011-06-15
• [Presentation] 慢性腎臓病(CKD)例での血中α-Klotho(sα-KL)濃度の検討 (2011)
  • Author(s): 左官弘和, 中谷公彦, ら
  • Organizer: 日本腎臓学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2011-06-15
• [Presentation] Decline of Renal Klotho Expression Is Associated with Hypercalciuria in Patients with Diabetes. (2010)
  • Author(s): Asai O, Nakatani K, et al.
  • Organizer: The 43th Annual Meeting of the American Society of Nephrology
  • Place of Presentation: Denver
  • Year and Date: 2010-11-18
• [Presentation] 糖尿病性腎症では早期腎症より尿中カルシウム排泄が増加するが,腎臓でのKlotho遺伝子発現低下が関与する (2010)
  • Author(s): 浅井 修、中谷公彦, 他
  • Organizer: 第53回日本腎臓学会学術総会
  • Place of Presentation: 神戸
  • Year and Date: 2010-06-16
• [Presentation] 糖尿病性腎症では早期腎症より尿中カルシウム排泄が増加するが, 腎臓でのKlotho遺伝子発現低下が関与する (2010)
  • Author(s): 浅井修, 中谷公彦, ら
  • Organizer: 日本腎臓学会総会
  • Place of Presentation: 神戸
  • Year and Date: 2010-06-16
• [Remarks]
  • URL: http://www.naramed-u.ac.jp/~lint/
• [Remarks]
  • URL: http://www.naramed-u.ac.jp/~lint/