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Rat pancreatectomy combined with isoprenaline or uninephrectomy as models of diabetic cardiomyopathy or nephropathy
Scientific Reports ( IF 3.8 ) Pub Date : 2020-09-30 , DOI: 10.1038/s41598-020-73046-8
Louise Thisted 1, 2 , Mette V Østergaard 1 , Annemarie A Pedersen 1 , Philip J Pedersen 1 , Ross T Lindsay 1, 3, 4 , Andrew J Murray 3 , Lisbeth N Fink 1 , Tanja X Pedersen 1, 5 , Thomas Secher 1 , Thea T Johansen 1, 6 , Sebastian T Thrane 1 , Torben Skarsfeldt 7 , Jacob Jelsing 1 , Morten B Thomsen 2 , Nora E Zois 1
Affiliation  

Cardiovascular and renal complications are the predominant causes of morbidity and mortality amongst patients with diabetes. Development of novel treatments have been hampered by the lack of available animal models recapitulating the human disease. We hypothesized that experimental diabetes in rats combined with a cardiac or renal stressor, would mimic diabetic cardiomyopathy and nephropathy, respectively. Diabetes was surgically induced in male Sprague Dawley rats by 90% pancreatectomy (Px). Isoprenaline (Iso, 1 mg/kg, sc., 10 days) was administered 5 weeks after Px with the aim of inducing cardiomyopathy, and cardiac function and remodeling was assessed by echocardiography 10 weeks after surgery. Left ventricular (LV) fibrosis was quantified by Picro Sirius Red and gene expression analysis. Nephropathy was induced by Px combined with uninephrectomy (Px-UNx). Kidney function was assessed by measurement of glomerular filtration rate (GFR) and urine albumin excretion, and kidney injury was evaluated by histopathology and gene expression analysis. Px resulted in stable hyperglycemia, hypoinsulinemia, decreased C-peptide, and increased glycated hemoglobin (HbA1c) compared with sham-operated controls. Moreover, Px increased heart and LV weights and dimensions and caused a shift from α-myosin heavy chain (MHC) to β-MHC gene expression. Isoprenaline treatment, but not Px, decreased ejection fraction and induced LV fibrosis. There was no apparent interaction between Px and Iso treatment. The superimposition of Px and UNx increased GFR, indicating hyperfiltration. Compared with sham-operated controls, Px-UNx induced albuminuria and increased urine markers of kidney injury, including neutrophil gelatinase-associated lipocalin (NGAL) and podocalyxin, concomitant with upregulated renal gene expression of NGAL and kidney injury molecule 1 (KIM-1). Whereas Px and isoprenaline separately produced clinical endpoints related to diabetic cardiomyopathy, the combination of the two did not accentuate disease development. Conversely, Px in combination with UNx resulted in several clinical hallmarks of diabetic nephropathy indicative of early disease development.



中文翻译:


大鼠胰腺切除联合异丙肾上腺素或单肾切除作为糖尿病心肌病或肾病模型



心血管和肾脏并发症是糖尿病患者发病和死亡的主要原因。由于缺乏能够概括人类疾病的动物模型,新疗法的开发受到阻碍。我们假设大鼠实验性糖尿病与心脏或肾脏应激源相结合,将分别模拟糖尿病性心肌病和肾病。通过 90% 胰腺切除术(Px)对雄性 Sprague Dawley 大鼠进行手术诱发糖尿病。 Px 后 5 周给予异丙肾上腺素(Iso,1 mg/kg,皮下注射,10 天),目的是诱发心肌病,术后 10 周通过超声心动图评估心脏功能和重构。通过 Picro Sirius Red 和基因表达分析对左心室 (LV) 纤维化进行量化。 Px联合单肾切除术(Px-UNx)诱发肾病。通过测量肾小球滤过率(GFR)和尿白蛋白排泄来评估肾功能,并通过组织病理学和基因表达分析来评估肾损伤。与假手术对照组相比,Px 导致稳定的高血糖、低胰岛素血症、C 肽减少和糖化血红蛋白 (HbA1c) 增加。此外,Px 增加了心脏和左心室的重量和尺寸,并导致 α-肌球蛋白重链 (MHC) 基因表达转变为 β-MHC 基因表达。异丙肾上腺素治疗可降低射血分数并诱导左心室纤维化,而 Px 则不然。 Px 和 Iso 处理之间没有明显的相互作用。 Px 和 UNx 的叠加增加了 GFR,表明过度滤过。 与假手术对照相比,Px-UNx 诱导白蛋白尿和肾损伤尿液标志物增加,包括中性粒细胞明胶酶相关脂质运载蛋白 (NGAL) 和足萼蛋白,同时上调 NGAL 和肾损伤分子 1 (KIM-1) 的肾脏基因表达。虽然 Px 和异丙肾上腺素分别产生与糖尿病心肌病相关的临床终点,但两者的组合并没有加剧疾病的发展。相反,Px 与 UNx 组合导致糖尿病肾病的多种临床特征,表明早期疾病的发展。

更新日期:2020-09-30
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