Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine , Kaohsiung , Taiwan.
Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital , Kaohsiung , Taiwan.
Am J Physiol Renal Physiol. 2018 Dec 1;315(6):F1720-F1731. doi: 10.1152/ajprenal.00536.2017. Epub 2018 Sep 19.
High levels of serum free fatty acids (FFAs) and proteinuria have been implicated in the pathogenesis of obesity-related nephropathy. CD36, a class B scavenger receptor, is highly expressed in the renal proximal tubules and mediates FFA uptake. It is not clear whether FFA- and proteinuria-mediated CD36 activation coordinates NLRP3 inflammasomes to induce renal tubular injury and inflammation. In this study, we investigated the roles of CD36 and NLRP3 inflammasomes in FFA-induced renal injury in high-fat diet (HFD)-induced obesity. HFD-fed C57BL/6 mice and palmitate-treated HK2 renal tubular cells were used as in vivo and in vitro models. Immunohistochemical staining showed that CD36, IL-1β, and IL-18 levels increased progressively in the kidneys of HFD-fed mice. Sulfo- N-succinimidyl oleate (SSO), a CD36 inhibitor, attenuated the HFD-induced upregulation of NLRP3, IL-1β, and IL-18 and suppressed the colocalization of NLRP3 and ASC in renal tubular cells. In vitro, SSO abolished the palmitate-induced activation of IL-1β, IL-18, and caspase-1 in HK2 proximal tubular cells. Furthermore, treatment with SSO and the knockdown of caspase-1 expression by siRNA both inhibited palmitate-induced cell death and apoptosis in HK2 cells. Collectively, palmitate causes renal tubular inflammation, cell death, and apoptosis via the CD36/NLRP3/caspase-1 axis, which may explain, at least in part, the mechanism underlying FFA-related renal tubular injury. The blockade of CD36-induced cellular processes is therefore a promising strategy for treating obesity-related nephropathy.
高血清游离脂肪酸 (FFA) 和蛋白尿与肥胖相关肾病的发病机制有关。CD36 是一种 B 类清道夫受体，在肾脏近端小管中高度表达，并介导 FFA 的摄取。目前尚不清楚 FFA 和蛋白尿介导的 CD36 激活是否协调 NLRP3 炎性体诱导肾小管损伤和炎症。在这项研究中，我们研究了 CD36 和 NLRP3 炎性体在高脂肪饮食 (HFD) 诱导肥胖小鼠中 FFA 诱导的肾损伤中的作用。HFD 喂养的 C57BL/6 小鼠和棕榈酸处理的 HK2 肾小管细胞分别作为体内和体外模型。免疫组织化学染色显示，CD36、IL-1β 和 IL-18 水平在 HFD 喂养小鼠的肾脏中逐渐升高。CD36 抑制剂磺基-N-琥珀酰亚胺辛酯 (SSO) 减弱了 HFD 诱导的 NLRP3、IL-1β 和 IL-18 的上调，并抑制了 NLRP3 和 ASC 在肾小管细胞中的共定位。在体外，SSO 消除了棕榈酸诱导的 HK2 近端肾小管细胞中 IL-1β、IL-18 和半胱天冬酶-1 的激活。此外，SSO 处理和 caspase-1 的 siRNA 表达下调均抑制了 HK2 细胞中棕榈酸诱导的细胞死亡和凋亡。综上所述，棕榈酸通过 CD36/NLRP3/caspase-1 轴引起肾小管炎症、细胞死亡和凋亡，这至少部分解释了 FFA 相关肾小管损伤的机制。因此，阻断 CD36 诱导的细胞过程可能是治疗肥胖相关肾病的一种有前途的策略。
