Kashyap Sonu, Engel Sean, Osman Mazen, Al-Saiegh Yousif, Wongjarupong Asarn, Grande Joseph P
Department of Laboratory Medicine and Pathology, Mayo Clinic , Rochester, MN , USA.
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA; Wartburg College, Waverly, IA, United States.
PeerJ. 2016 Feb 22;4:e1736. doi: 10.7717/peerj.1736. eCollection 2016.
Purpose. Type 2 diabetes is the leading cause of end stage renal disease in the United States. Atherosclerotic renal artery stenosis is commonly observed in diabetic patients and impacts the rate of renal and cardiovascular disease progression. We sought to test the hypothesis that renovascular hypertension, induced by unilateral renal artery stenosis, exacerbates cardiac remodeling in leptin-deficient (db/db) mice, which serves as a model of human type II diabetes. Methods. We employed a murine model of renovascular hypertension through placement of a polytetrafluoroethylene cuff on the right renal artery in db/db mice. We studied 109 wild-type (non-diabetic, WT) and 95 db/db mice subjected to renal artery stenosis (RAS) or sham surgery studied at 1, 2, 4, and 6+ weeks following surgery. Cardiac remodeling was assessed by quantitative analysis of the percent of myocardial surface area occupied by interstitial fibrosis tissue, as delineated by trichrome stained slides. Aortic pathology was assessed by histologic sampling of grossly apparent structural abnormalities or by section of ascending aorta of vessels without apparent abnormalities. Results. We noted an increased mortality in db/db mice subjected to RAS. The mortality rate of db/db RAS mice was about 23.5%, whereas the mortality rate of WT RAS mice was only 1.5%. Over 60% of mortality in the db/db mice occurred in the first two weeks following RAS surgery. Necropsy showed massive intrathoracic hemorrhage associated with aortic dissection, predominantly in the ascending aorta and proximal descending aorta. Aortas from db/db RAS mice showed more smooth muscle dropout, loss of alpha smooth muscle actin expression, medial disruption, and hemorrhage than aortas from WT mice with RAS. Cardiac tissue from db/db RAS mice had more fibrosis than did cardiac tissue from WT RAS mice. Conclusions. db/db mice subjected to RAS are prone to develop fatal aortic dissection, which is not observed in WT mice with RAS. The db/db RAS model provides the basis for future studies directed towards defining basic mechanisms underlying the interaction of hypertension and diabetes on the development of aortic lesions.
目的。2型糖尿病是美国终末期肾病的主要病因。动脉粥样硬化性肾动脉狭窄在糖尿病患者中很常见，并影响肾脏和心血管疾病的进展速度。我们试图验证这样一个假设，即单侧肾动脉狭窄诱发的肾血管性高血压会加剧瘦素缺乏（db/db）小鼠的心脏重塑，该小鼠可作为人类II型糖尿病的模型。方法。我们通过在db/db小鼠的右肾动脉上放置聚四氟乙烯袖带，建立了肾血管性高血压的小鼠模型。我们研究了109只野生型（非糖尿病，WT）小鼠和95只接受肾动脉狭窄（RAS）或假手术的db/db小鼠，在术后1、2、4和6周以上进行观察。通过对三色染色切片所描绘的间质纤维化组织占据心肌表面积百分比的定量分析来评估心脏重塑。通过对明显结构异常进行组织学取样或对无明显异常的血管升主动脉进行切片来评估主动脉病变。结果。我们注意到接受RAS的db/db小鼠死亡率增加。db/db RAS小鼠的死亡率约为23.5%，而WT RAS小鼠的死亡率仅为1.5%。db/db小鼠超过60%的死亡发生在RAS手术后的前两周。尸检显示大量胸腔内出血与主动脉夹层有关，主要发生在升主动脉和近端降主动脉。与WT RAS小鼠的主动脉相比，db/db RAS小鼠的主动脉显示出更多的平滑肌缺失、α平滑肌肌动蛋白表达丧失、中膜破坏和出血。db/db RAS小鼠的心脏组织比WT RAS小鼠的心脏组织有更多的纤维化。结论。接受RAS的db/db小鼠容易发生致命的主动脉夹层，而在接受RAS的WT小鼠中未观察到这种情况。db/db RAS模型为未来研究确定高血压和糖尿病相互作用对主动脉病变发展的基本机制提供了基础。
