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Research ArticleDrug Discovery and Translational Medicine

RNA Interference Targeting Liver Angiopoietin-Like Protein 3 Protects from Nephrotic Syndrome in a Rat Model Via Amelioration of Pathologic Hypertriglyceridemia

Yitong Zhao, Masaki Goto, Nosratola D. Vaziri, Mahyar Khazaeli, Han Liu, Nazli Farahanchi, Elham Khanifar, Ted Farzaneh, Patrick A. Haslett, Hamid Moradi and Mangala M. Soundarapandian
Journal of Pharmacology and Experimental Therapeutics March 2021, 376 (3) 428-435; DOI: https://doi.org/10.1124/jpet.120.000257
Yitong Zhao
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.)
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Masaki Goto
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.)
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Nosratola D. Vaziri
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.)
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Mahyar Khazaeli
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.)
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Han Liu
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.)
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Nazli Farahanchi
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.)
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Elham Khanifar
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.)
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Ted Farzaneh
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.)
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Patrick A. Haslett
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.)
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Hamid Moradi
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.)
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Mangala M. Soundarapandian
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.)
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Abstract

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 ANGPTL3 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 Angptl3 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 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 RNA interference to suppress hepatic Angptl3 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.

Footnotes

    • Received July 29, 2020.
    • Accepted December 4, 2020.
  • Y.Z. and M.G. contributed equally to this work.

  • This work was supported by Alnylam Pharmaceuticals by a grant to N.D.V.

  • M.S. and P.H. are employees and stockholders of Alnylam Pharmaceuticals. No author has an actual or perceived conflict of interest with the contents of this article.

  • https://doi.org/10.1124/jpet.120.000257.

  • Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 376 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 376, Issue 3
1 Mar 2021
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Research ArticleDrug Discovery and Translational Medicine

Angptl3 siRNA Treatment of Nephrotic Syndrome

Yitong Zhao, Masaki Goto, Nosratola D. Vaziri, Mahyar Khazaeli, Han Liu, Nazli Farahanchi, Elham Khanifar, Ted Farzaneh, Patrick A. Haslett, Hamid Moradi and Mangala M. Soundarapandian
Journal of Pharmacology and Experimental Therapeutics March 1, 2021, 376 (3) 428-435; DOI: https://doi.org/10.1124/jpet.120.000257

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Research ArticleDrug Discovery and Translational Medicine

Angptl3 siRNA Treatment of Nephrotic Syndrome

Yitong Zhao, Masaki Goto, Nosratola D. Vaziri, Mahyar Khazaeli, Han Liu, Nazli Farahanchi, Elham Khanifar, Ted Farzaneh, Patrick A. Haslett, Hamid Moradi and Mangala M. Soundarapandian
Journal of Pharmacology and Experimental Therapeutics March 1, 2021, 376 (3) 428-435; DOI: https://doi.org/10.1124/jpet.120.000257
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