Department of Anatomy, Faculty of Medicine, Umm Al-Qura University, Makkah, 24230, Saudi Arabia.
Department of Human Anatomy and Embryology, Faculty of Medicine, Zagazig University, Zagazig, Egypt.
Free Radic Biol Med. 2022 Mar;182:150-159. doi: 10.1016/j.freeradbiomed.2022.02.024. Epub 2022 Feb 24.
Chronic kidney disease (CKD) is an important global disease its rates are increasing worldwide. CKD is caused by injuries to kidney tissue that exceeds the rate of regeneration, which with time lead to irreversible renal damage and CKD become evident. In females, diminished estrogen supply in the postmenopausal period is associated with greater risk for developing CKD. In this study we isolated exosomes from bone marrow mesenchymal stem/stromal cells (BM-MSCs) and tested their therapeutic effects on post-menopause CKD (PM-CKD) and compared their effects with BM-MSCs. The menopause model was achieved by bilateral ovariectomy in 8-months-old female albino rats, then no treatment, 2 million BM-MSCs or 100 μg of exosomes (Exo) was given intravenously in tail vein to ovariectomized rats and the study continued for 8 weeks post-ovariectomy. Changes in weight, urine volume, urine protein content, kidney function biochemical parameters (creatinine and BUN), Kidney oxidative stress (MDA), kidney antioxidant parameters (SOD, GPx and CAT), histopathological changes, immunohistochemical expression of KIM-1 and, finally, genes related to renal damage (peroxiredoxin-3, KIM-1 and ICAM-1) and inflammation (TNF-α, Cox2 and IL-6) were recorded for all study groups. Post-ovariectomy there was an increased body weight, drastic reduction of estrogen and progesterone levels, reduced urine output, increased urinary protein excretion, elevated serum creatinine and BUN, increased MDA and reduced GPx SOD, and CAT in kidney tissue, chronic inflammation, degenerative and fibrotic lesions in histopathological examination, high expression of KIM-1 immunohistochemically and changes in gene expression analyses all pointing to the development of CKD in the study rats. In the PM-CKD groups receiving BM-MSCs or Exo, the whole chronic inflammatory picture was completely reversed towards a much normal kidney structure and function. The improvements were more observable with Exo compared to BM-MSCs. Overall, our results show for the first time that exosomes isolated from BM-MSCs are more potent in reducing chronic inflammatory changes in the kidney of postmenopausal females compared to the cell-based approach using BM-MSCs. Therefore, MSCs-derived exosomes are a promising therapeutic approach for preserving postmenopausal kidney structure and function and, subsequently, should improve the quality of life of postmenopausal females.
慢性肾脏病（CKD）是一种重要的全球性疾病，其发病率在全球范围内呈上升趋势。CKD 是由肾脏组织损伤引起的，其损伤速度超过了再生速度，随着时间的推移，会导致不可逆转的肾损伤，CKD 也变得明显。在女性中，绝经后雌激素供应减少与发生 CKD 的风险增加有关。在这项研究中，我们从骨髓间充质干细胞（BM-MSCs）中分离出外泌体，并测试了它们对绝经后 CKD（PM-CKD）的治疗效果，并将其与 BM-MSCs 进行了比较。通过在 8 月龄雌性白化大鼠双侧卵巢切除术建立绝经模型，然后给予静脉注射 200 万个 BM-MSCs 或 100μg 外泌体（Exo），并在卵巢切除后继续研究 8 周。记录所有研究组的体重变化、尿量、尿蛋白含量、肾功能生化参数（肌酐和 BUN）、肾脏氧化应激（MDA）、肾脏抗氧化参数（SOD、GPx 和 CAT）、组织病理学变化、KIM-1 的免疫组化表达，最后，与肾脏损伤相关的基因（过氧化物酶 3、KIM-1 和 ICAM-1）和炎症（TNF-α、Cox2 和 IL-6）的基因表达分析。卵巢切除术后，大鼠体重增加，雌激素和孕激素水平急剧下降，尿量减少，尿蛋白排泄增加，血清肌酐和 BUN 升高，肾脏组织 MDA 升高，SOD、GPx 和 CAT 降低，组织病理学检查发现慢性炎症、退行性和纤维性病变，KIM-1 的免疫组化表达升高，基因表达分析也表明研究大鼠发生了 CKD。在接受 BM-MSCs 或 Exo 的 PM-CKD 组中，整个慢性炎症表现完全逆转，肾脏结构和功能更接近正常。与 BM-MSCs 相比，Exo 的改善更为明显。总的来说，我们的研究结果首次表明，与基于 BM-MSCs 的细胞治疗方法相比，从 BM-MSCs 中分离的外泌体在减少绝经后女性肾脏慢性炎症变化方面更有效。因此，MSC 衍生的外泌体是一种有前途的治疗方法，可以保持绝经后肾脏的结构和功能，从而提高绝经后女性的生活质量。
