Alasmari Wardah A, Abdelfattah-Hassan Ahmed, El-Ghazali Hanaa M, Abdo Samar A, Ibrahim Doaa, ElSawy Naser A, El-Shetry Eman S, Saleh Ayman A, Abourehab Mohammed A S, Mahfouz Hala
Department of Anatomy, Faculty of Medicine, Umm Al-Qura University, Makkah 24230, Saudi Arabia.
Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, Egypt.
Biomolecules. 2022 May 2;12(5):663. doi: 10.3390/biom12050663.
The rate of chronic kidney disease (CKD) is increasing globally, and it is caused by continuous damage to kidney tissue. With time the renal damage becomes irreversible, leading to CKD development. In females, post-menopause lack of estrogen supply has been described as a risk factor for CKD development, and studies targeting post-menopause CKD are scarce. In the present study, we used exosomes isolated from bone marrow mesenchymal stem/stromal cells (BM-MSCs) to test their therapeutic potential against the development of CKD. At first, the menopause model was achieved by surgical bilateral ovariectomy in female albino rats. After that, 100 µg of exosomes was given to ovariectomized rats, and the study continued for 2 months. Changes in urine volume, urine protein content, kidney function biochemical parameters (creatinine and BUN), kidney antioxidant parameters (SOD, GPx and CAT), histological changes, immunohistochemical levels of caspase 3, and the gene expression of NGAL (related to kidney damage), TGFβ1 and αSMA (related to fibrosis and EMT), and caspase 3 (related to apoptosis) were studied. After the ovariectomy, the occurrence of CKD was confirmed in the rats by the drastic reduction of serum estrogen and progesterone levels, reduced urine output, increased urinary protein excretion, elevated serum creatinine and BUN, reduced GPx SOD, and CAT in kidney tissue, degenerative and fibrotic lesions in the histopathological examination, higher immunohistochemical expression of caspase 3 and increased expression of all studied genes. After exosomes administration, the entire chronic inflammatory picture in the kidney was corrected, and a near-normal kidney structure and function were attained. This study shows for the first time that BM-MSCs exosomes are potent for reducing apoptosis and fibrosis levels and, thus, can reduce the chronic damage of the kidneys in females that are in their menopause period. Therefore, MSCs-derived exosomes should be considered a valuable therapy for preserving postmenopausal kidney structure and function and, subsequently, could improve the quality of females' life during menopause.
全球慢性肾脏病（CKD）的发病率正在上升，其由肾组织的持续损伤引起。随着时间的推移，肾损伤会变得不可逆转，从而导致CKD的发展。在女性中，绝经后雌激素供应不足被描述为CKD发展的一个危险因素，而针对绝经后CKD的研究很少。在本研究中，我们使用从骨髓间充质干/基质细胞（BM-MSCs）中分离的外泌体来测试它们对CKD发展的治疗潜力。首先，通过对雌性白化大鼠进行双侧卵巢切除术建立绝经模型。之后，给卵巢切除的大鼠注射100μg外泌体，并持续研究2个月。研究了尿量、尿蛋白含量、肾功能生化参数（肌酐和尿素氮）、肾脏抗氧化参数（超氧化物歧化酶、谷胱甘肽过氧化物酶和过氧化氢酶）、组织学变化、半胱天冬酶3的免疫组化水平，以及中性粒细胞明胶酶相关脂质运载蛋白（与肾损伤相关）、转化生长因子β1和α平滑肌肌动蛋白（与纤维化和上皮-间质转化相关）和半胱天冬酶3（与细胞凋亡相关）的基因表达。卵巢切除术后，通过血清雌激素和孕酮水平急剧降低、尿量减少、尿蛋白排泄增加、血清肌酐和尿素氮升高、肾脏组织中谷胱甘肽过氧化物酶、超氧化物歧化酶和过氧化氢酶降低、组织病理学检查中的退行性和纤维化病变、半胱天冬酶3的免疫组化表达升高以及所有研究基因的表达增加，证实大鼠发生了CKD。给予外泌体后，肾脏中的整个慢性炎症情况得到纠正，肾脏结构和功能接近正常。本研究首次表明，BM-MSCs外泌体能够有效降低细胞凋亡和纤维化水平，从而可以减少处于绝经期女性的肾脏慢性损伤。因此，应将间充质干细胞衍生的外泌体视为一种有价值的治疗方法，以维持绝经后肾脏的结构和功能，进而改善女性绝经期间的生活质量。
