Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China; Institute of Nephrology, Peking University, Beijing, China; Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China; Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China.
The Institute of Cardiovascular Sciences, Institute of Systems Biomedicine, School of Basic Medical Sciences, Beijing, China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China; Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Beijing, China; Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China; Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China.
Kidney Int. 2021 Jul;100(1):107-121. doi: 10.1016/j.kint.2021.02.025. Epub 2021 Mar 3.
Since failed resolution of inflammation is a major contributor to the progression of diabetic nephropathy, identifying endogenously generated molecules that promote the physiological resolution of inflammation may be a promising therapeutic approach for this disease. Annexin A1 (ANXA1), as an endogenous mediator, plays an important role in resolving inflammation. Whether ANXA1 could affect established diabetic nephropathy through modulating inflammatory states remains largely unknown. In the current study, we found that in patients with diabetic nephropathy, the levels of ANXA1 were upregulated in kidneys, and correlated with kidney function as well as kidney outcomes. Therefore, the role of endogenous ANXA1 in mouse models of diabetic nephropathy was further evaluated. ANXA1 deficiency exacerbated kidney injuries, exhibiting more severe albuminuria, mesangial matrix expansion, tubulointerstitial lesions, kidney inflammation and fibrosis in high fat diet/streptozotocin-induced-diabetic mice. Consistently, ANXA1 overexpression ameliorated kidney injuries in mice with diabetic nephropathy. Additionally, we found Ac2-26 (an ANXA1 mimetic peptide) had therapeutic potential for alleviating kidney injuries in db/db mice and diabetic Anxa1 knockout mice. Mechanistic studies demonstrated that intracellular ANXA1 bound to the transcription factor NF-κB p65 subunit, inhibiting its activation thereby modulating the inflammatory state. Thus, our data indicate that ANXA1 may be a promising therapeutic approach to treating and reversing diabetic nephropathy.
由于炎症反应的持续存在是导致糖尿病肾病进展的主要原因，因此，寻找内源性的能够促进炎症消退的分子可能是治疗该疾病的一种有前景的方法。膜联蛋白 A1（ANXA1）作为一种内源性介质，在炎症消退中发挥着重要作用。然而，ANXA1 是否可以通过调节炎症状态来影响已建立的糖尿病肾病尚不清楚。在本研究中，我们发现糖尿病肾病患者肾脏中 ANXA1 的水平上调，并与肾功能以及肾脏结局相关。因此，进一步评估了内源性 ANXA1 在糖尿病肾病小鼠模型中的作用。ANXA1 缺乏会加重肾脏损伤，在高脂肪饮食/链脲佐菌素诱导的糖尿病小鼠中表现出更严重的蛋白尿、系膜基质扩张、肾小管间质病变、肾脏炎症和纤维化。同样，糖尿病肾病小鼠中过表达 ANXA1 可改善肾脏损伤。此外，我们发现 Ac2-26（一种 ANXA1 模拟肽）对 db/db 小鼠和糖尿病 Anxa1 敲除小鼠的肾脏损伤具有治疗潜力。机制研究表明，细胞内的 ANXA1 与转录因子 NF-κB p65 亚基结合，抑制其激活，从而调节炎症状态。因此，我们的数据表明，ANXA1 可能是治疗和逆转糖尿病肾病的一种有前途的方法。
