Kashyap Sonu, Warner Gina, Hu Zeng, Gao Feng, Osman Mazen, Al Saiegh Yousif, Lien Karen R, Nath Karl, Grande Joseph P
Department of Laboratory Medicine & Pathology, Mayo Clinic, Rochester, Minnesota, United States of America.
Kogod Aging Center, Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota, United States of America.
PLoS One. 2017 Oct 26;12(10):e0187062. doi: 10.1371/journal.pone.0187062. eCollection 2017.
Renovascular hypertension (RVH) has deleterious effects on both the kidney and the heart. TGF-β signaling through Smad3 directs tissue fibrosis in chronic injury models. In the 2-kidney 1-clip (2K1C) model of RVH, employing mice on the 129 genetic background, Smad3 deficiency (KO) protects the stenotic kidney (STK) from development of interstitial fibrosis. However, these mice have an increased incidence of sudden cardiac death following 2K1C surgery. The purpose of this study was to characterize the cardiovascular phenotype of these mice. Renal artery stenosis (RAS) was established in Wild-type (WT) and Smad3 KO mice (129 genetic background) by placement of a polytetrafluoroethylene cuff on the right renal artery. Mortality was 25.5% for KO mice with RAS, 4.1% for KO sham mice, 1.2% for WT with RAS, and 1.8% for WT sham mice. Myocardial tissue of mice studied at 3 days following surgery showed extensive myocyte necrosis in KO but not WT mice. Myocyte necrosis was associated with a rapid induction of Ccl2 expression, macrophage influx, and increased MMP-9 activity. At later time points, both KO and WT mice developed myocardial fibrosis. No aortic aneurysms or dissections were observed at any time point. Smad3 KO mice were backcrossed to the C57BL/6J strain and subjected to RAS. Sudden death was observed at 10-14 days following surgery in 62.5% of mice; necropsy revealed aortic dissections as the cause of death. As observed in the 129 mice, the STK of Smad3 KO mice on the C57BL/6J background did not develop significant chronic renal damage. We conclude that the cardiovascular manifestations of Smad3 deficient mice are strain-specific, with myocyte necrosis in 129 mice and aortic rupture in C57BL/6J mice. Future studies will define mechanisms underlying this strain-specific effect on the cardiovascular system.
肾血管性高血压（RVH）对肾脏和心脏均有有害影响。在慢性损伤模型中，通过Smad3的转化生长因子-β信号传导指导组织纤维化。在采用129遗传背景小鼠的RVH 2肾1夹（2K1C）模型中，Smad3缺陷（KO）可保护狭窄肾脏（STK）免于间质纤维化的发展。然而，这些小鼠在2K1C手术后心脏性猝死的发生率增加。本研究的目的是描述这些小鼠的心血管表型。通过在右肾动脉上放置聚四氟乙烯袖带，在野生型（WT）和Smad3 KO小鼠（129遗传背景）中建立肾动脉狭窄（RAS）。RAS的KO小鼠死亡率为25.5%，KO假手术小鼠为4.1%，WT伴RAS小鼠为1.2%，WT假手术小鼠为1.8%。术后3天研究的小鼠心肌组织显示，KO小鼠而非WT小鼠出现广泛的心肌细胞坏死。心肌细胞坏死与Ccl2表达的快速诱导、巨噬细胞浸润和MMP-9活性增加有关。在后期时间点，KO和WT小鼠均发生心肌纤维化。在任何时间点均未观察到主动脉瘤或夹层。将Smad3 KO小鼠回交至C57BL/6J品系并进行RAS。术后10 - 14天，62.5%的小鼠出现猝死；尸检显示主动脉夹层是死亡原因。如在129小鼠中观察到的，C57BL/6J背景的Smad3 KO小鼠的STK未发生明显的慢性肾损伤。我们得出结论，Smad3缺陷小鼠的心血管表现具有品系特异性，129小鼠表现为心肌细胞坏死，C57BL/6J小鼠表现为主动脉破裂。未来的研究将确定这种对心血管系统的品系特异性影响的潜在机制。
