Huang Wen, Liu Hua, Zhu Shuang, Woodson Michael, Liu Rong, Tilton Ronald G, Miller Jordan D, Zhang Wenbo
Department of Healthcare, Qianfoshan Hospital Affiliated to Shandong University, Jinan, China.
Department of Ophthalmology, University of Texas Medical Branch, Galveston, TX 77555, USA.
Aging (Albany NY). 2017 Mar 28;9(3):1069-1083. doi: 10.18632/aging.101214.
Aging is associated with an increased incidence and prevalence of renal glomerular diseases. Sirtuin (Sirt) 6, a nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase, has been shown to protect against multiple age-associated phenotypes; however it is unknown whether Sirt6 has a direct pathophysiologic role in the kidney. In the present study, we demonstrate that Sirt6 is expressed in the kidney and aging Sirt6-deficient mice exhibit renal hypertrophy with glomerular enlargement. Sirt6 deletion induces podocyte injury, including decreases in slit diaphragm proteins, foot process effacement, and cellular loss, resulting in proteinuria. Knockdown of Sirt6 in cultured primary murine podocytes induces shape changes with loss of process formation and cell apoptosis. Moreover, Sirt6 deficiency results in progressive renal inflammation and fibrosis. Collectively, these data provide compelling evidence that Sirt6 is important for podocyte homeostasis and maintenance of glomerular function, and warrant further investigation into the role of Sirt6 in age-associated kidney dysfunction.
衰老与肾小球疾病的发病率和患病率增加相关。沉默调节蛋白（Sirt）6是一种烟酰胺腺嘌呤二核苷酸（NAD）依赖性组蛋白脱乙酰酶，已被证明可抵御多种与年龄相关的表型；然而，Sirt6在肾脏中是否具有直接的病理生理作用尚不清楚。在本研究中，我们证明Sirt6在肾脏中表达，衰老的Sirt6基因敲除小鼠表现出肾肥大伴肾小球增大。Sirt6缺失会诱导足细胞损伤，包括裂孔隔膜蛋白减少、足突消失和细胞丢失，从而导致蛋白尿。在原代培养的小鼠足细胞中敲低Sirt6会诱导形态改变，导致突起形成丧失和细胞凋亡。此外，Sirt6缺乏会导致进行性肾炎症和纤维化。总体而言，这些数据提供了令人信服的证据，表明Sirt6对足细胞稳态和肾小球功能的维持很重要，值得进一步研究Sirt6在与年龄相关的肾功能障碍中的作用。
