硝基油酸与氯沙坦对糖尿病肾病的影响：甲状旁腺激素相关蛋白的调节作用

The effect of nitro-oleic versus losartan in diabetic nephropathy: modulation of parathyroid hormone-related protein.

作者信息

Mohammed A S, Sadek N B, Eshra M A, Khowailed E A H, Rashed L A, Aboulhoda B E

机构信息

Department of Physiology, Faculty of Medicine, Cairo University, Egypt.

Department of Biochemistry, Faculty of Medicine, Cairo University, Egypt.

出版信息

Folia Morphol (Warsz). 2019;78(1):79-90. doi: 10.5603/FM.a2018.0057. Epub 2018 Jul 16.

DOI:10.5603/FM.a2018.0057

PMID:30009367

Abstract

BACKGROUND

Parathyroid hormone-related protein (PTHrP) involvement in the mechanisms related to angiotensin II (AngII)-induced renal injury has become an emerging concern. The current study was thus designed to compare the possible preventive and therapeutic effect of AngII antagonists, losartan and nitro-oleic (NO2-OA) acid, on diabetic nephropathy (DN) and evaluate their effect on PTHrP modulation as well as on the functional and histopathological parameters in the kidney of diabetic rats.

MATERIALS AND METHODS

Forty eight adult male Sprague Dawley rats were divided into control group, DN group, pre-diabetic nephropathy (pre-DN) losartan group, pre-diabetic nephropathy nitro-oleic acid (pre-DN NO2-OA) group, post-diabetic nephropathy (post-DN) losartan and post-diabetic nephropathy nitro-oleic acid (post-DN NO2-OA) groups. At the end of the study, systolic blood pressure (SBP), serum fasting glucose, glomerular filtration rate (GFR), urea, urea albumin excretion (UAE), serum angiotensin, renal PTHrP gene expression and correlations between PTHrP and SBP, serum glucose, AngII and kidney functions were evaluated. Histo- logical examination, Masson's trichrome, periodic acid-Schiff staining as well as morphometric analysis and histopathological scoring for tubular and glomerular parameters have been carried out.

RESULTS

Prophylactic losartan and NO2-OA were associated with improvement in SBP, serum glucose, urea, GFR, UAE, with reduction in serum AngII and PTHrP overexpression observed in diabetic kidney. Treatment with losartan and NO2-OA showed the same effect except that post-DN NO2-OA showed no significant effect regarding kidney function. Strong correlations were observed between PTHrP and SBP, serum glucose, AngII and kidney functions. Histopathological results revealed obvious improvement in glomerulosclerosis, vascular and tubular injury parameters in prophylactic groups especially with losartan.

CONCLUSIONS

Both pre and post-DN losartan, NO2-OA may have a potential role in protection and regression of DN through reduction of PTHrP overexpression.

摘要

背景

甲状旁腺激素相关蛋白（PTHrP）参与血管紧张素II（AngII）诱导的肾损伤相关机制已成为一个新的关注点。因此，本研究旨在比较AngII拮抗剂氯沙坦和硝基油酸（NO2 - OA）对糖尿病肾病（DN）可能的预防和治疗作用，并评估它们对PTHrP调节以及对糖尿病大鼠肾脏功能和组织病理学参数的影响。

材料与方法

48只成年雄性Sprague Dawley大鼠分为对照组、DN组、糖尿病前期肾病（pre - DN）氯沙坦组、糖尿病前期肾病硝基油酸（pre - DN NO2 - OA）组、糖尿病后期肾病（post - DN）氯沙坦组和糖尿病后期肾病硝基油酸（post - DN NO2 - OA）组。在研究结束时，评估收缩压（SBP）、血清空腹血糖、肾小球滤过率（GFR）、尿素、尿白蛋白排泄量（UAE）、血清血管紧张素、肾脏PTHrP基因表达以及PTHrP与SBP、血清葡萄糖、AngII和肾功能之间的相关性。进行了组织学检查、Masson三色染色、过碘酸 - 希夫染色以及肾小管和肾小球参数的形态计量分析和组织病理学评分。

结果

预防性给予氯沙坦和NO2 - OA可使SBP、血清葡萄糖、尿素、GFR、UAE得到改善，糖尿病肾脏中血清AngII和PTHrP过表达降低。氯沙坦和NO2 - OA治疗显示出相同的效果，除了post - DN NO2 - OA对肾功能无显著影响。观察到PTHrP与SBP、血清葡萄糖、AngII和肾功能之间有很强的相关性。组织病理学结果显示，预防性给药组尤其是氯沙坦组的肾小球硬化、血管和肾小管损伤参数有明显改善。