TY - JOUR T1 - RNAi targeting liver Angiopoietin-like protein 3 protects from nephrotic syndrome in a rat model via amelioration of pathologic hypertriglyceridemia JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.120.000257 SP - JPET-AR-2020-000257 AU - Yitong Zhao AU - Masaki Goto AU - Nosratola D Vaziri AU - Mahyar Khazaeli AU - Han Liu AU - Nazli Farahanchi AU - Elham Khanifar AU - Ted Farzaneh AU - Patrick A Haslett AU - Hamid Moradi AU - Mangala M Soundarapandian Y1 - 2020/01/01 UR - http://jpet.aspetjournals.org/content/early/2020/12/17/jpet.120.000257.abstract N2 - 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), a Lipoprotein Lipase (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 ANGPTL3 by RNA interference (RNAi) 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-conjugated small-interfering RNA (siRNA) to selectively target and suppress liver Angptl3 in rats with puromycin-induceded NS which exhibit clinical features of NS including proteinuria, hypoalbuminemia, hyperlipidemia and renal histological abnormalities. The study demonstrated that siRNA-mediated knockdown of the liver Angptl3 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 Angptl3 is protective in NS and points to the possibility that the use of RNAi to suppress hepatic Angptl3 can serve as a novel therapeutic strategy for NS. Significance Statement 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 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. ER -