Vitamin D and Diabetic Nephropathy

描述（由申请人提供）：糖尿病肾病是糖尿病的主要长期并发症，糖尿病是终末期肾脏疾病的最常见原因，在美国与最高死亡率相关。糖尿病肾病的特点是肾小球和小管上皮肥大、蛋白尿、肾小球硬化和小管间质纤维化。肾内肾素-血管紧张素系统（RAS）和TGF-¿已被证明在糖尿病肾病的发病机制中发挥关键作用。1,25-二羟维生素D3是肾脏产生的主要内分泌激素，靶向肾脏，具有抗增殖活性和RAS的内分泌抑制作用。维生素d缺乏与肾衰竭及相关并发症有关；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和肾损伤中起保护作用。为了验证这一假设，我们提出了三个具体目标。第一个目的是明确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生成的分子机制，重点关注肾内RAS和TGF-¿信号；第二个目的是研究维生素D受体（VDR）在预防糖尿病肾病中的作用，使用链脲佐菌素（STZ）诱导的糖尿病VDR敲除小鼠和缺乏VDR的糖尿病db/db小鼠；第三个目的是探索低钙维生素D类似物对stz诱导的糖尿病C57BL6小鼠和自发性糖尿病db/db小鼠高血糖诱导的肾损伤的保护作用。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具有肾保护作用，而且几乎没有钙血症副作用。这些探索性研究将增强我们对维生素D生理学的一个新方面的理解，并为探索维生素D类似物在预防和治疗糖尿病肾病方面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.