Treatment of Kidney Disease in Diabetes and Obesity

项目摘要/摘要 肥胖和糖尿病是美国心血管和肾脏疾病的主要原因。 这一点越来越令人担忧，因为肥胖和胰岛素抵抗的发生率正在增加 预计到2030年，每4名美国人中就有1人患有糖尿病。尽管有所有有益的干预措施 在糖尿病患者中实施，包括严格的血糖控制，严格的血压控制，血管紧张素 转换酶抑制或血管紧张素II受体拮抗，肾脏疾病进展在大多数这些 病人。调节肥胖和肥胖发病途径的其他治疗方式 因此，迫切需要糖尿病肾病来减缓糖尿病患者肾脏疾病的进展 肥胖和糖尿病。 我们实验室的研究表明，用高活性和特异性的TGR5治疗糖尿病小鼠 激动剂可预防糖尿病肾病的进展。激活TGR5的有益效果是 与雌激素相关受体(ERR)和sirtuin3(SIRT3)的刺激有关。 在这个方案中，我们将检验以下假设：1)TGR5在肾脏的调节中起重要作用 糖尿病和肥胖中的疾病；2)TGR5抑制加速和TGR5激活防止肥胖和 糖尿病肾病；3)TGR5的有益作用部分是通过刺激ERR来实现的。 在特定目标1中，我们将确定肾脏特异性TGR5缺失在肥胖肾脏疾病中的作用 还有糖尿病。在特定的目标2中，我们将确定肾脏特异性TGR5过表达的影响 肾脏疾病中的肥胖和糖尿病。在具体目标3中，我们将确定TGR5在 肾脏疾病在肥胖和糖尿病中的调节依赖于肾脏特异性错误的激活。 影响：TGR5和ERR在调节肥胖和糖尿病肾病中的潜在作用是非常新颖的 并将对肥胖和糖尿病相关肾脏并发症的治疗产生重大影响。TGR5 和ERR？具有明显的调节线粒体生物发生、能量代谢和能量的作用 支出：因此，它们与用于治疗糖尿病及其相关疾病的其他干预措施截然不同。 TGR5还可以减轻体重和预防肥胖的并发症。

PROJECT SUMMARY/ABSTRACT Obesity and diabetes mellitus is the leading cause of cardiovascular and renal disease in the United States. This is of increasing concern since the incidence of obesity and insulin resistance is increasing and as many as 1 in 4 Americans are expected to have diabetes by the year 2030. In spite of all the beneficial interventions implemented in patients with diabetes, including tight glucose control, tight blood pressure control, angiotensin converting enzyme inhibition or angiotensin II receptor antagonism, renal disease progresses in most of these patients. Additional treatment modalities that modulate the pathogenesis pathways involved in obesity and diabetic nephropathy are therefore urgently needed to slow the progression of renal disease in patients with obesity and diabetes. Studies from our laboratory indicate that treatment of diabetic mice with a highly active and specific TGR5 agonist prevents the progression of diabetic nephropathy. The beneficial effects of TGR5 activation are associated with stimulation of estrogen-related receptor ¿ (ERR¿) and sirtuin 3 (SIRT3). In this proposal we will test the hypotheses that: 1) TGR5 plays an important role in modulation of kidney disease in diabetes and obesity; 2) TGR5 inhibition accelerates and TGR5 activation prevents obesity and diabetic kidney disease; 3) the beneficial effects of TGR5 are mediated in part through stimulation of ERR¿. In Specific Aim 1 we will determine the effects of kidney specific TGR5 deletion in kidney disease in obesity and diabetes. In Specific Aim 2 we will determine the effects of kidney specific TGR5 overexpression in kidney disease in obesity and diabetes. In Specific Aim 3 we will determine whether the effect of TGR5 in modulation of kidney disease in obesity and diabetes is dependent on kidney specific ERR¿ activation. Impact: The potential role of TGR5 and ERR¿ in modulating obesity and diabetic renal disease is very novel and will have major implications for the treatment of obesity and diabetes related renal complications. TGR5 and ERR¿ have distinct actions of regulating mitochondrial biogenesis, energy metabolism and energy expenditure: they are therefore quite distinct from other interventions used in treatment of diabetes and its complications where TGR5 can also induce weight loss and prevent obesity.