A Reproducible Mouse Model of Moderate CKD With Early Manifestations of Osteoblastic Transition of Cardiovascular System.
A Reproducible Mouse Model of Moderate CKD With Early Manifestations of Osteoblastic Transition of Cardiovascular System.
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DOI：
10.3389/fphys.2022.897179
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发表时间：
2022
影响因子：
4
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中科院分区：
文献类型：
--
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慢性肾脏疾病(CKD)是一个重大的公共卫生挑战，与死亡、发病率和卫生保健支出相关的风险很大。导致慢性肾脏病发展和进展的罪魁祸首是多方面的，本质上是异质性的。这一概念强调了动物模型多样化的必要性，以研究其病理生理学、相关并发症，并随后发现新的治疗方法。重要的是，迫切需要能够概括男女CKD并发症的动物模型。心血管疾病是CKD患者最常见的死亡原因，部分原因可能是血管钙化(VC)的高患病率。本研究以易患Vc的DBA/2小鼠为模型，探讨单侧肾缺血再灌注加对侧肾切除(UIRI/NX)复制CKD及其相关并发症的可行性和重复性。我们的结果表明，无论性别，小鼠都忠实地表现出UIRI/NX后中度CKD的并发症，表现为血清肌酐显著升高，蛋白尿显著增加，胶原沉积程度增加，经典纤维化标志物表达增加，循环中成纤维细胞生长因子-23、甲状旁腺素和海普西丁水平升高。此外，基于较高水平的成骨标志物，即CBFA-1、骨桥蛋白、骨钙素和Osterix，我们证实了主动脉平滑肌细胞和心肌细胞的成骨转化。我们的数据证实了一种可行的、一致的中度慢性肾脏病及其相关并发症的模型，在雄性和雌性小鼠中都是如此。此外，该模型中心血管系统成骨细胞转化的早期证据证实了该模型适合于研究和实施该领域迫切需要的潜在预防和/或治疗方法。
Chronic kidney disease (CKD) is a significant public health challenge with a substantial associated risk of mortality, morbidity, and health care expenditure. Culprits that lead to development and progression of CKD are multifaceted and heterogenous in nature. This notion underscores the need for diversification of animal models to investigate its pathophysiology, related complications, and to subsequently enable discovery of novel therapeutics. Importantly, animal models that could recapitulate complications of CKD in both genders are desperately needed. Cardiovascular disease is the most common cause of death in CKD patients that may be due in part to high prevalence of vascular calcification (VC). Using DBA/2 mice that are susceptible to development of VC, we sought to investigate the feasibility and reproducibility of a unilateral ischemia-reperfusion model followed by contralateral nephrectomy (UIRI/Nx) to induce CKD and its related complications in female and male mice. Our results demonstrate that irrespective of gender, mice faithfully displayed complications of moderate CKD following UIRI/Nx as evidenced by significant rise in serum creatinine, albuminuria, higher degree of collagen deposition, elevated expression of classic fibrotic markers, higher circulating levels of FGF-23, PTH and hepcidin. Moreover, we corroborate the osteoblastic transition of aortic smooth muscle cells and cardiomyocytes based on higher levels of osteoblastic markers namely, Cbfa-1, osteopontin, osteocalcin, and osterix. Our data confirms a viable, and consistent model of moderate CKD and its associated complications in both male and female mice. Furthermore, early evidence of osteoblastic transition of cardiovascular system in this model confirms its suitability for studying and implementing potential preventive and/or therapeutic approaches that are urgently needed in this field.
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