Study on Mechanisms for Progression and Regression of Diabetic Glomerular Injury and Role of Novel Humoral Factors

糖尿病肾小球损伤进展和消退机制及新型体液因子作用的研究

• 批准号: 17590826
• 负责人: MUKOYAMA Masashi
• 金额: $ 2.24万
• 依托单位: Kyoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590826/
• 关键词: Diabetic nephropathy; CCN family; Leptin; Transgenic mouse; Podocyte; CTGF; Cyr61; Natriuretic peptide; 細胞外基質

In order to explore the mechanisms for progression and regression of diabetic glomerular injury and to investigate the roles of novel humoral factors in such processes, we examined the in vivo effects of the CCN family (CCN1, CCN2) that are extracellular matrix-associated secretory proteins, fat tissue-derived hormone leptin, and cardiac hormone natriuretic peptides, using genetically engineered mouse models.CCN1 (connective tissue growth factor, CTGF), a profibrotic protein mediating fibrogenic properties of TGF-β, is expressed normally in glomerular podocytes and upregulated in diabetic nephropathy. We established the podocyte-specific CTGF-transgenic (Tg) mice using human nephrin promoter, and examined effects of CTGF overexpression in the diabetic milieu. CTGF-Tg mice did not show any abnormality at basal state, but exhibited significantly enhanced proteinuria (〜3-fold) compared with wild-type mice during the course of streptozotocin (STZ)-induced diabetic nephropathy. CTGF-Tg mice … More also showed more pronounced mesangial expansion, with decreased number and vacuolar changes of podocytes, indicating aggravation of podocyte injury. In contrast, CCN2 (cysteine-rich protein 61, Cyr61), another podocyte-derived humoral factor, is suggested to have renoprotective properties. In podocyte-specific Cyr61-Tg mice with the nephrin promoter, glomerular hypertrophy was less prominent during STZ-induced diabetes as compared with wild-type mice.We then investigated renal abnormalities in A-ZIP/F-1 mice, a lipoatrophic diabetes model. This mouse model revealed markedly progressive nephrotic-range proteinuria, remarkable glomerular hypertrophy with mesangial expansion, and glomerular basement membrane thickening, which are characteristics of human diabetic nephropathy at advanced stages. Transgenic overexpression of the leptin gene or pharmacological administration of leptin into this model almost completely normalized such abnormal phenotypes. Finally, chronic overproduction of brain natriuretic peptide (BNP) in BNP-Tg mice was significantly resistant against diabetic glomerular injury in terms of proteinuria, mesangial expansion, and mesangial upregulation of the ERK/TGF-β cascade. These findings suggest the therapeutic potential of leptin and natriuretic peptides in diabetic nephropathy. Less

为了探索糖尿病肾小球损伤进展和消退的机制，并研究新的体液因子在这些过程中的作用，我们检测了CCN家族的体内作用（CCN 1，CCN 2），它们是细胞外基质相关分泌蛋白、脂肪组织衍生的激素瘦素和心脏激素利钠肽。结缔组织生长因子（结缔组织生长因子，CTGF），一种介导TGF-β的纤维化性质的促纤维化蛋白，在肾小球足细胞中正常表达，并在糖尿病肾病中上调。我们建立了足细胞特异性CTGF转基因（Tg）小鼠使用人类nephrin启动子，并检查CTGF过表达在糖尿病环境中的影响。CTGF-Tg小鼠在基础状态下没有表现出任何异常，但在链脲佐菌素（STZ）诱导的糖尿病肾病过程中，与野生型小鼠相比，CTGF-Tg小鼠的蛋白尿显著增加（约1.3倍）。CTGF-Tg小鼠 ...更多信息 也显示更明显的系膜扩张，足细胞数量减少和空泡化，表明足细胞损伤加重。相反，CCN 2（富含半胱氨酸的蛋白质61，Cyr 61），另一个足细胞衍生的体液因子，被认为具有肾脏保护特性。在足细胞特异性Cyr 61-Tg小鼠nephrin启动子，肾小球肥大是不太突出，在STZ诱导的糖尿病相比，野生型mice.We然后研究了肾脏异常的A-ZIP/F-1小鼠，脂肪萎缩性糖尿病模型。该小鼠模型显示了显著进行性肾病范围蛋白尿、显著肾小球肥大伴系膜扩张和肾小球基底膜增厚，这些是晚期人类糖尿病肾病的特征。瘦素基因的转基因过表达或瘦素的药理学给药到这个模型中几乎完全正常化这种异常表型。最后，在BNP-Tg小鼠中脑钠肽（BNP）的慢性过度产生在蛋白尿、系膜扩张和ERK/TGF-β级联的系膜上调方面对糖尿病肾小球损伤具有显著抵抗性。这些发现表明瘦素和利钠肽在糖尿病肾病中的治疗潜力。少

项目成果

Prevention and reversal of renal injury by leptin in a new mouse model of diabetic nephropathy

瘦素预防和逆转新型糖尿病肾病小鼠模型的肾损伤

• 发表时间: 2004
• 期刊: FASEB J 19
• 作者: Qiao;Y.;Suganami T
• 通讯作者: Suganami T

The neuroprotective and vasculo-neuro-regenerative roles of adrenomedullin in ischemic brain and its therapeutic potential

• DOI: 10.1210/en.2005-1038
• 发表时间: 2006-04-01
• 期刊: ENDOCRINOLOGY
• 影响因子: 4.8
• 作者: Miyashita, K;Itoh, H;Nakao, K
• 通讯作者: Nakao, K

Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury.

• DOI: 10.1172/jci23056
• 发表时间: 2005-03
• 期刊: The Journal of clinical investigation
• 作者: K. Mori;H. Lee;Dana Rapoport;Ian R. Drexler;Kirk Foster;Jun Yang;K. Schmidt-Ott;Xia Chen;Jau-yi Li;Stacey Weiss;J. Mishra;F. Cheema;G. Markowitz;T. Suganami;K. Sawai;M. Mukoyama;C. Kunis;V. D’Agati;P. Devarajan;J. Barasch

Redistribution of connexin43 expression in glomerular podocytes predicts poor renal prognosis in patients with type 2 diabetes and overt nephropathy.

• DOI: 10.1093/ndt/gfl260
• 发表时间: 2006-09
• 期刊: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
• 作者: K. Sawai;M. Mukoyama;K. Mori;H. Yokoi;M. Koshikawa;T. Yoshioka;Ryuji Takeda;A. Sugawara;T. Kuwahara;M. Saleem;O. Ogawa;K. Nakao

Transgenic overexpression of brain natriuretic peptide prevents the progression of diabetic nephropathy in mice

• DOI: 10.1007/s00125-006-0352-y
• 发表时间: 2006-10-01
• 期刊: DIABETOLOGIA
• 影响因子: 8.2
• 作者: Makino, H.;Mukoyama, M.;Nakao, K.
• 通讯作者: Nakao, K.