Treatment of Kidney Disease in Diabetes and Obesity

描述（由申请人提供）：肥胖和糖尿病是美国心血管和肾脏疾病的主要原因。由于肥胖和胰岛素抵抗的发病率正在增加，预计到2030年，多达四分之一的美国人将患有糖尿病，因此这一点越来越受到关注。尽管在糖尿病患者中实施了所有有益的干预措施，包括严格的葡萄糖控制、严格的血压控制、血管紧张素转换酶抑制或血管紧张素II受体拮抗剂，但这些患者中的大多数仍发生肾病进展。因此，迫切需要调节肥胖和糖尿病肾病发病机制途径的其他治疗方式，以减缓肥胖和糖尿病患者的肾脏疾病进展。我们实验室的研究表明，用高活性和特异性TGR 5激动剂治疗糖尿病小鼠可预防糖尿病肾病的进展。TGR 5激活的有益作用与雌激素相关受体（ERR）和sirtuin 3（SIRT 3）的刺激有关。在这项提案中，我们将测试以下假设：1）TGR 5在糖尿病和肥胖症肾脏疾病的调节中起重要作用; 2）TGR 5抑制加速和TGR 5激活预防肥胖和糖尿病肾脏疾病; 3）TGR 5的有益作用部分通过刺激ERR β介导。在具体目标1中，我们将确定肾脏特异性TGR 5缺失在肥胖和糖尿病肾病中的作用。在具体目标2中，我们将确定肾脏特异性TGR 5过表达在肥胖和糖尿病肾病中的作用。在具体目标3中，我们将确定TGR 5在调节肥胖和糖尿病肾病中的作用是否依赖于肾脏特异性ERR β激活。影响：TGR 5和ERR β在调节肥胖和糖尿病肾病中的潜在作用是非常新颖的，将对肥胖和糖尿病相关肾脏并发症的治疗产生重大影响。TGR 5和ERR β具有调节线粒体生物发生、能量代谢和能量消耗的独特作用：因此，它们与用于治疗糖尿病及其并发症的其他干预措施截然不同，其中TGR 5也可以诱导体重减轻和预防肥胖。

DESCRIPTION (provided by applicant): 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.