The Diabetes & Metabolism Lab, Baruch Padeh Poriya Medical Center, Lower Galilee, Israel.
Ophthalmology, Baruch Padeh Poriya Medical Center, Lower Galilee, Israel.
J Diabetes Res. 2020 Nov 26;2020:7907605. doi: 10.1155/2020/7907605. eCollection 2020.
Diabetic nephropathy (DN) is one of the most common microvascular complications of diabetes and is the leading cause of end-stage renal disease (ESRD) and replacement therapy worldwide. Vitamin D levels in DN patients are very low due to the decrease in the synthesis and activity of 1- hydroxylase in the proximal tubule cells and decrease in the vitamin D receptor abundance. To date, few studies have shown the antioxidant effects of 1,25-dihydroxyvitamin D [1,25(OH)D] on hyperglycemia-induced renal injury. The selective activator of the vitamin D receptor, paricalcitol, reduces proteinuria and slows the progression of kidney injury. The precise mechanism through which vitamin D affects diabetic status and provides kidney protection remains to be determined.
Diabetes mellitus (DM) was induced in 94 8-week-old DBA/2J mice by intraperitoneal injection of streptozotocin (STZ). DM mice were randomly divided into receiving vehicle or treatment with paricalcitol, the active vitamin D analog, 1 week after DM induction or paricalcitol treatment 3 weeks after DM induction. An additional control group of healthy wild-type mice was not treated. Urine albumin, blood urea nitrogen, and creatinine levels were measured before and at the end of the paricalcitol treatment. Periodic acid-Schiff, immunohistochemistry staining, and western blot of the renal tissues of vitamin D receptor, villin, nephrin, and podocin expressions, were analyzed.
Paricalcitol treatment restored villin, nephrin, and podocin protein levels that were downregulated upon DM induction, and reduced fibronectin protein level. Vitamin D receptor activation by paricalcitol may reduce proteinuria of DN in mice and alleviate high-glucose-induced injury of kidney podocytes by regulating the key molecules such nephrin-podocin.
Paricalcitol treatment was associated with improved structural changes in type 1 diabetic mice including upregulation of vitamin D receptor expression, and decreased fibrosis markers such as fibronectin. These effects may contribute to the consistent benefit of vitamin D analog to slow the deterioration in glomerular function and reduce the risk of ESRD in patients with type 1 and 2 diabetes mellitus. Our results suggest that additional use of paricalcitol may be beneficial in treating patients with diabetes under standard therapeutic strategies.
糖尿病肾病（DN）是糖尿病最常见的微血管并发症之一，也是全球范围内终末期肾病（ESRD）和替代治疗的主要原因。由于近端肾小管细胞 1-羟化酶的合成和活性降低以及维生素 D 受体丰度降低，DN 患者的维生素 D 水平非常低。迄今为止，很少有研究表明 1,25-二羟维生素 D [1,25(OH)D]对高血糖诱导的肾损伤具有抗氧化作用。维生素 D 受体的选择性激活剂帕立骨化醇可减少蛋白尿并减缓肾损伤的进展。维生素 D 影响糖尿病状态并提供肾脏保护的确切机制仍有待确定。
通过腹腔注射链脲佐菌素（STZ）将 94 只 8 周龄 DBA/2J 小鼠诱导为糖尿病。在 DM 诱导后 1 周或 DM 诱导后 3 周给予帕立骨化醇治疗时，将 DM 小鼠随机分为接受载体或治疗的亚组。未接受治疗的健康野生型小鼠为另一个对照组。在帕立骨化醇治疗前后测量尿白蛋白、血尿素氮和肌酐水平。分析肾组织中维生素 D 受体、微管相关蛋白、nephrin 和 podocin 的表达的过碘酸-希夫、免疫组织化学染色和 Western blot。
帕立骨化醇治疗恢复了 DM 诱导后下调的微管相关蛋白、nephrin 和 podocin 蛋白水平，并降低了纤维连接蛋白水平。帕立骨化醇对维生素 D 受体的激活可能通过调节 nephrin-podocin 等关键分子减少 DN 小鼠的蛋白尿，并减轻高糖诱导的肾足细胞损伤。
帕立骨化醇治疗与 1 型糖尿病小鼠的结构变化改善相关，包括维生素 D 受体表达上调，以及纤维化标志物如纤维连接蛋白减少。这些作用可能有助于维生素 D 类似物对肾小球功能恶化的持续益处，并降低 1 型和 2 型糖尿病患者发生 ESRD 的风险。我们的结果表明，在标准治疗策略下，额外使用帕立骨化醇可能对糖尿病患者有益。
