Vitamin D and Diabetic Nephropathy

描述(申请人提供)：糖尿病肾病是糖尿病的主要长期并发症，是导致终末期肾病的最常见原因，并与美国最高的死亡率有关。糖尿病肾病以肾小球和肾小管上皮细胞肥大、蛋白尿、肾小球硬化和肾小管间质纤维化为特征。肾素-血管紧张素系统(RAS)和转化生长因子-β在糖尿病肾病的发病机制中起重要作用。1，25-二羟基维生素D3是一种主要由肾脏产生并以肾脏为靶点的内分泌激素，具有抗增殖活性，是RAS的内分泌抑制因子。维生素D缺乏与肾功能衰竭和相关并发症有关；然而，维生素D在糖尿病肾病中的作用尚不清楚。根据最近的证据和我们的初步研究，我们假设1，25-二羟基维生素D3在糖尿病肾病的发病机制和肾脏损害中起保护作用。为了检验这一假设，我们提出了三个具体目标。第一个目的是确定1，25-二羟基维生素D3抑制高糖诱导的系膜细胞增殖和细胞外基质产生的分子机制，重点是肾内RAS和转化生长因子-β信号转导；第二个目的是利用链脲佐菌素(STZ)诱导的糖尿病VDR基因敲除小鼠和缺乏VDR的糖尿病db/db小鼠，研究维生素D受体(VDR)在糖尿病肾病保护中的作用；第三个目的是探讨低钙维生素D类似物在STZ诱导的糖尿病C57BL6小鼠和自发性糖尿病db/db小鼠中对抗高血糖诱导的肾脏损伤的治疗潜力。我们的初步数据表明，用这种类似物治疗STZ诱导的正常小鼠确实提供了肾脏保护，几乎没有钙化副作用。这些探索性研究将加深我们对维生素D生理学新方面的理解，并为探索维生素D类似物在预防和治疗糖尿病肾病中的治疗潜力提供基础。

DESCRIPTION (provided by applicant): Diabetic nephropathy is a major long-term complication of diabetic mellitus, which is the most common cause of end-stage renal disease and associated with the highest mortality in the US. Diabetic nephropathy is characterized by glomerular and tubuloepithelial hypertrophy, albuminuria, and glomerulosclerosis and tubulointerstitial fibrosis. The intrarenal renin-angiotensin system (RAS) and TGF-¿ have been shown to play a critical role in the pathogenesis of diabetic nephropathy. As a major endocrine hormone produced by the kidney and targeting the kidney, 1,25-dihydroxyvitmain D3, possesses anti-proliferative activity and functions as an endocrine suppressor of the RAS. vitamin D-deficiency has been linked to renal failure and associated complications; however, the role of vitamin D in diabetic nephropathy is unknown. Based on recent evidence and our preliminary studies we hypothesize that 1,25-dihydroxyvitamin D3 plays a protective role in the pathogenesis and renal injury of diabetic nephropathy. To test this hypothesis, we propose three specific aims. The first aim is to define the molecular mechanism whereby 1,25-dihydroxyvitmain D3 inhibits high glucose-induced mesangial cell proliferation and extracelluar matrix production, focusing on the intrarenal RAS and TGF- ¿ signaling; the second aim is to study the role of the vitamin D receptor (VDR) in the protection against diabetic nephropathy, using streptozotocin (STZ)-induced diabetic VDR knockout mice and diabetic db/db mice that lack the VDR; the third aim is to explore the therapeutic potential of low calcemic vitamin D analogs in the protection against hyperglycamia-induced renal injury in STZ-induced diabetic C57BL6 mice and in spontaneous diabetic db/db mice. Our preliminary data have demonstrated that treatment of STZ- induced normal mice with such an analog indeed offers renal protection with little calcemic side effect. These exploratory studies will enhance our understanding of a novel aspect of vitamin D physiology and provide a basis for exploring the therapeutic potential of vitamin D analogs in prevention and treatment of diabetic nephropathy.