Division of Nephrology and Hypertension, University of California, Irvine, California (Y.Z., M.G., N.D.V., M.K., H.L., N.F., H.M.); Long Beach Memorial Pathology Group, Long Beach, California (E.K.); Department of Pathology and Laboratory Medicine, University of California, Irvine, California (T.F.); Tibor Rubin VA Medical Center, Department of Medicine, Nephrology Section, Long Beach, California (H.M.); and Alnylam Pharmaceuticals Inc, Cambridge, Massachusetts (P.A.H., M.M.S.).
Division of Nephrology and Hypertension, University of California, Irvine, California (Y.Z., M.G., N.D.V., M.K., H.L., N.F., H.M.); Long Beach Memorial Pathology Group, Long Beach, California (E.K.); Department of Pathology and Laboratory Medicine, University of California, Irvine, California (T.F.); Tibor Rubin VA Medical Center, Department of Medicine, Nephrology Section, Long Beach, California (H.M.); and Alnylam Pharmaceuticals Inc, Cambridge, Massachusetts (P.A.H., M.M.S.)
J Pharmacol Exp Ther. 2021 Mar;376(3):428-435. doi: 10.1124/jpet.120.000257. Epub 2020 Dec 18.
Nephrotic syndrome (NS) is associated with metabolic perturbances including profound dyslipidemia characterized by hypercholesterolemia and hypertriglyceridemia. A major underlying mechanism of hypertriglyceridemia in NS is lipoprotein lipase (LPL) deficiency and dysfunction. There is emerging evidence that elevated angiopoietin-like protein 3 (ANGPTL3), an LPL inhibitor that is primarily expressed and secreted by hepatocytes, may be in part responsible for these findings. Furthermore, there is evidence pointing to the contribution of ANGPTL3 to the pathogenesis of proteinuria in NS. Therefore, we hypothesized that inhibition of hepatic by RNA interference will ameliorate dyslipidemia and other symptoms of NS and pave the way for a new therapeutic strategy. To this end, we used a subcutaneously delivered, GalNAc (N-Acetylgalactosamine)-conjugated small interfering RNA (siRNA) to selectively target and suppress liver in rats with puromycin-induced NS, which exhibits clinical features of NS including proteinuria, hypoalbuminemia, hyperlipidemia, and renal histologic abnormalities. The study demonstrated that siRNA-mediated knockdown of the liver relieved its inhibitory effect on LPL and significantly reduced hypertriglyceridemia in nephrotic rats. This was accompanied by diminished proteinuria and hypoalbuminemia, which are the hallmarks of NS, and significant attenuation of renal tissue inflammation and oxidative stress. Taken together, this study confirmed the hypothesis that suppression of is protective in NS and points to the possibility that the use of RNA interference to suppress hepatic can serve as a novel therapeutic strategy for NS. SIGNIFICANCE STATEMENT: The current standard of care for mitigating nephrotic dyslipidemia in nephrotic syndrome is statins therapy. However, the efficacy of statins and its safety in the context of impaired kidney function is not well established. Here, we present an alternate therapeutic approach by using siRNA targeting Angptl3 expressed in hepatocytes. As the liver is the major source of circulating Angptl3, siRNA treatment reduced the profound hypertriglyceridemia in a rat model of nephrotic syndrome and was also effective in improving kidney and cardiac function.
肾病综合征（NS）与代谢紊乱有关，包括以高胆固醇血症和高三酰甘油血症为特征的严重血脂异常。NS 中高三酰甘油血症的一个主要潜在机制是脂蛋白脂肪酶（LPL）缺乏和功能障碍。有新的证据表明，升高的血管生成素样蛋白 3（ANGPTL3），一种主要由肝细胞表达和分泌的 LPL 抑制剂，可能在一定程度上导致了这些发现。此外，有证据表明 ANGPTL3 有助于 NS 蛋白尿的发病机制。因此，我们假设通过 RNA 干扰抑制肝脏 可以改善 NS 的血脂异常和其他症状，并为新的治疗策略铺平道路。为此，我们使用皮下给予的 GalNAc（N-乙酰半乳糖胺）缀合的小干扰 RNA（siRNA），选择性地靶向和抑制嘌呤霉素诱导的 NS 大鼠的肝脏 ，该大鼠表现出 NS 的临床特征，包括蛋白尿、低白蛋白血症、高脂血症和肾脏组织学异常。研究表明，siRNA 介导的肝脏 敲低减轻了其对 LPL 的抑制作用，并显著降低了肾病大鼠的高三酰甘油血症。这伴随着蛋白尿和低白蛋白血症的减少，这是 NS 的标志，以及肾脏组织炎症和氧化应激的显著减弱。总之，这项研究证实了抑制 对 NS 具有保护作用的假设，并指出使用 RNA 干扰抑制肝脏 可能成为 NS 的一种新的治疗策略。意义陈述：目前治疗肾病综合征肾病性血脂异常的标准治疗方法是他汀类药物治疗。然而，在肾功能受损的情况下，他汀类药物的疗效及其安全性尚未得到很好的确定。在这里，我们提出了一种替代的治疗方法，使用针对肝细胞中表达的 Angptl3 的 siRNA。由于肝脏是循环 ANGPTL3 的主要来源，siRNA 治疗降低了肾病综合征大鼠模型中的严重高三酰甘油血症，并且还有效地改善了肾脏和心脏功能。
