Gonadectomy prevents the increase in blood pressure and glomerular injury in angiotensin-converting enzyme 2 knockout diabetic male mice. Effects on renin-angiotensin system
Gonadectomy prevents the increase in blood pressure and glomerular injury in angiotensin-converting enzyme 2 knockout diabetic male mice. Effects on renin-angiotensin system
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DOI：
10.1097/hjh.0000000000001015
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发表时间：
2016-09-01
影响因子：
4.9
通讯作者：
Riera, Marta
中科院分区：
文献类型：
--
作者：
Clotet, Sergi;Soler, Maria Jose;Riera, Marta
背景：血管紧张素转换酶2 （ACE2）缺失加重肾损伤，其扩增可改善糖尿病肾病。在我们的环境中，男性增加了慢性肾脏疾病的发病率、患病率和进展。方法：研究ACE2缺乏和性腺切除术（GDX）对糖尿病肾病的影响及其与纤维化、蛋白激酶B （Akt）激活、肾素-血管紧张素系统（RAS）若干组分表达的关系。小鼠注射链脲佐菌素诱导糖尿病，随访19周。研究了加GDX和不加GDX的野生型和ACE2敲除（ACE2KO）雄性小鼠的生理和肾脏参数。结果：与糖尿病野生型相比，糖尿病ACE2KO表现为血压（BP）升高、肾小球损伤和肾纤维化。促性腺切除术后的糖尿病患者ACE2KO血压下降。在缺乏ACE2的情况下，GDX可减轻蛋白尿和肾脏病变，如系膜基质扩张和足细胞丢失。糖尿病ACE2KO小鼠肾皮质a-平滑肌肌动蛋白积累和胶原沉积均显著减少，而糖尿病野生型小鼠肾皮质a-平滑肌肌动蛋白积累和胶原沉积均显著减少。GDX还能降低ACE2KO小鼠的循环ACE活性。ACE2缺失改变了GDX对糖尿病小鼠RAS皮质基因表达的影响。在对照组和糖尿病性ACE2KO小鼠中，肾脏皮质Akt磷酸化水平因糖尿病和ACE2缺失而升高，因GDX而降低，但在野生型小鼠中没有。结论：我们的研究结果提示，在糖尿病和ACE2缺乏的病理条件下，GDX可能在肾脏内发挥保护作用。这种肾保护可能归因于不同的机制，如血压的降低、RAS的调节和akt相关通路的下调。
Background: Angiotensin-converting enzyme 2 (ACE2) deletion worsens kidney injury, and its amplification ameliorates diabetic nephropathy. Male sex increases the incidence, prevalence, and progression of chronic kidney disease in our environment.Method: Here, we studied the effect of ACE2 deficiency and gonadectomy (GDX) on diabetic nephropathy and its relationship with fibrosis, protein kinase B (Akt) activation, and the expression of several components of the renin-angiotensin system (RAS). Mice were injected with streptozotocin to induce diabetes and followed for 19 weeks. Physiological and renal parameters were studied in wild-type and ACE2 knockout (ACE2KO) male mice with and without GDX.Results: Diabetic ACE2KO showed increased blood pressure (BP), glomerular injury, and renal fibrosis compared with diabetic wild-type. Gonadectomized diabetic ACE2KO presented a decrease in BP. In the absence of ACE2, GDX attenuated albuminuria and renal lesions, such as mesangial matrix expansion and podocyte loss. Both, a-smooth muscle actin accumulation and collagen deposition were significantly decreased in renal cortex of gonadectomized diabetic ACE2KO but not diabetic wild-type mice. GDX also reduced circulating ACE activity in ACE2KO mice. Loss of ACE2 modified the effect of GDX on cortical gene expression of RAS in diabetic mice. Akt phosphorylation in renal cortex was increased by diabetes and loss of ACE2 and decreased by GDX in control and diabetic ACE2KO but not in wild-type mice.Conclusions: Our results suggest that GDX may exert a protective effect within the kidney under pathological conditions of diabetes and ACE2 deficiency. This renoprotection may be ascribed to different mechanisms such as decrease in BP, modulation of RAS, and downregulation of Akt-related pathways.