Alonazi Asma S, Aloraini Rana M, Albulayhi Lama M, Alshehri Layal M, Bin Dayel Anfal F, Alamin Maha A, Aldamri Nouf T, Alshammari Tahani K, Alkhelb Dalal A, Sarawi Wedad S, Alghibiwi Hanan K, Alrasheed Nawal M, Elnagar Doaa M, Alrasheed Nouf M
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
Department of Zoology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia.
Int J Mol Sci. 2025 Apr 23;26(9):3990. doi: 10.3390/ijms26093990.
Cellular senescence is a hallmark of aging and contributes to age-related diseases, including diabetic nephropathy (DN). Additionally, macrophage-mediated inflammation has been linked with DKD. Therefore, we investigated the effect of macrophage depletion on kidney cell senescence in DN, focusing on the relationship between the GDF-15 and Klotho signaling pathways. Wistar albino rats ( = 24) were divided into four groups: healthy control, liposomal clodronate (LC)-treated healthy, diabetic, and LC-treated diabetic groups. Rats in the LC-treated healthy, diabetic, and LC-treated diabetic groups were intravenously administered LC once a week for 4 weeks. Rat models of type 2 diabetes were successfully established via the administration of streptozotocin and a high-fat diet, as evidenced by increased blood glucose levels, kidney weight to body weight (KW/BW) ratio, serum albumin, creatinine, and urea levels, kidney damage, and oxidative stress. However, LC-mediated macrophage depletion reduced the KW/BW ratio, improved serum and oxidative parameters, decreased inflammatory markers (IL-6 and TNF-α), and ameliorated oxidative stress. Additionally, LC treatment promoted macrophage polarization towards the anti-inflammatory phenotype, downregulated GDF-15 expression, upregulated Klotho expression, and ameliorated kidney damage. In conclusion, macrophage depletion combats kidney senescence by modulating Klotho and GDF-15, indicating their potential as novel targets in DN treatment.
细胞衰老为衰老的一个标志，并促成包括糖尿病肾病（DN）在内的与年龄相关的疾病。此外，巨噬细胞介导的炎症与糖尿病肾病（DKD）相关联。因此，我们研究了巨噬细胞耗竭对糖尿病肾病中肾细胞衰老的影响，重点关注生长分化因子15（GDF-15）与α-klotho信号通路之间的关系。将24只Wistar白化大鼠分为四组：健康对照组、经脂质体氯膦酸盐（LC）处理的健康组、糖尿病组和经LC处理的糖尿病组。经LC处理的健康组、糖尿病组和经LC处理的糖尿病组的大鼠每周静脉注射一次LC，共4周。通过给予链脲佐菌素和高脂饮食成功建立了2型糖尿病大鼠模型，血糖水平升高、肾重与体重（KW/BW）比值、血清白蛋白、肌酐和尿素水平、肾损伤以及氧化应激均证明了这一点。然而，LC介导的巨噬细胞耗竭降低了KW/BW比值，改善了血清和氧化参数，降低了炎症标志物（白细胞介素-6和肿瘤坏死因子-α），并减轻了氧化应激。此外，LC治疗促进巨噬细胞向抗炎表型极化，下调GDF-15表达，上调α-klotho表达，并减轻肾损伤。总之，巨噬细胞耗竭通过调节α-klotho和GDF-15对抗肾衰老，表明它们作为糖尿病肾病治疗新靶点的潜力。
