Qiu Lihua, Ma Zhaoxia, Li Jinyan, Wu Zhen, Dai Longmei, Long Ruimin, Hu Linlin, Sun Jianxiu, Hu Min, Li Yanjiao
Yunnan Key Laboratory for Basic Research on Bone and Joint Diseases, Kunming University, Kunming, China.
Yunnan Jici Institute for Regenerative Medicine Co., Ltd., Kunming, China.
PLoS One. 2024 Dec 11;19(12):e0315437. doi: 10.1371/journal.pone.0315437. eCollection 2024.
Renal interstitial fibrosis, a condition prevalent in aging humans and animals, is closely linked to the eventual development of renal failure. Establishing an animal model that exactly replicates the pathogenesis of renal interstitial fibrosis induced by natural aging in humans is crucial for advancing mechanistic studies and testing antifibrotic therapies. Implanted allogeneic or xenogeneic cells are cleared by the immune system when stem cell therapy is applied in nonimmunodeficient animal fibrosis models, affecting the effect of the intervention and making it difficult to demonstrate the survival, proliferation, differentiation, or secretion of the delivered autologous human-derived cells. This study effectively developed a model of spontaneous renal interstitial fibrosis linked to natural aging in 43-week-old NOD/SCID mice. Compared with those of 12- and 32-week-old mice, the kidneys of the model mice exhibited prominent fibrosis characteristics, accompanied by numerous fibrous septa and collagen deposition, increased COL1A1 expression, and decreased MMP9 expression. SA-β-gal activity and P21 gene expression levels increased, confirming renal cell senescence in the model mice. Additionally, an increase in α-SMA staining indicated an increase in epithelial-mesenchymal transition. More importantly, we observed TGF-β-SMAD3 pathway activation, mitochondrial dysfunction, decreased antioxidant capacity, oxidative stress, and an enhanced inflammatory response in the model group, consistent with renal interstitial fibrosis in elderly individuals. In this comprehensive investigation, we successfully developed a spontaneous mouse model of renal interstitial fibrosis and revealed the molecular pathways contributing to increased susceptibility to kidney injury and renal fibrosis in elderly individuals.
肾间质纤维化是一种在衰老的人类和动物中普遍存在的病症，与肾衰竭的最终发展密切相关。建立一个能够准确复制人类自然衰老所致肾间质纤维化发病机制的动物模型，对于推进机制研究和测试抗纤维化疗法至关重要。当在非免疫缺陷动物纤维化模型中应用干细胞疗法时，植入的同种异体或异种细胞会被免疫系统清除，这会影响干预效果，使得难以证明所递送的自体人源细胞的存活、增殖、分化或分泌情况。本研究成功建立了一种与43周龄NOD/SCID小鼠自然衰老相关的自发性肾间质纤维化模型。与12周龄和32周龄小鼠的肾脏相比，模型小鼠的肾脏呈现出明显的纤维化特征，伴有大量纤维间隔和胶原沉积，COL1A1表达增加，MMP9表达降低。SA-β-半乳糖苷酶活性和P21基因表达水平升高，证实模型小鼠存在肾细胞衰老。此外，α-SMA染色增加表明上皮-间质转化增加。更重要的是，我们观察到模型组中TGF-β-SMAD3信号通路激活、线粒体功能障碍、抗氧化能力降低、氧化应激以及炎症反应增强，这与老年人的肾间质纤维化情况一致。在这项全面的研究中，我们成功建立了一种自发性小鼠肾间质纤维化模型，并揭示了导致老年人肾损伤易感性增加和肾纤维化的分子途径。
