title: Chitosan/siRNA nanoparticles targeting cyclooxygenase type 2 attenuate unilateral ureteral obstruction-induced kidney injury in mice.
abstract: Cyclooxygenase type 2 (COX-2) plays a predominant role in the progression of kidney injury in obstructive nephropathy. The aim of this study was to test the efficacy of chitosan/small interfering RNA (siRNA) nanoparticles to knockdown COX-2 specifically in macrophages to prevent kidney injury induced by unilateral ureteral obstruction (UUO). Using optical imaging techniques and confocal microscopy, we demonstrated that chitosan/siRNA nanoparticles accumulated in macrophages in the obstructed kidney. Consistent with the imaging data, the obstructed kidney contained a higher amount of siRNA and macrophages. Chitosan-formulated siRNA against COX-2 was evaluated on RAW macrophages demonstrating reduced COX-2 expression and activity after LPS stimulation. Injection of COX-2 chitosan/siRNA nanoparticles in mice subjected to three-day UUO diminished the UUO-induced COX-2 expression. Likewise, macrophages in the obstructed kidney had reduced COX-2 immunoreactivity, and histological examination showed lesser tubular damage in COX-2 siRNA-treated UUO mice. Parenchymal inflammation, assessed by tumor necrosis factor-alpha (TNF-α) and interleukin 6 mRNA expression, was attenuated by COX-2 siRNA. Furthermore, treatment with COX-2 siRNA reduced heme oxygenase-1 and cleaved caspase-3 in UUO mice, indicating lesser oxidative stress and apoptosis. Our results demonstrate a novel strategy to prevent UUO-induced kidney damage by using chitosan/siRNA nanoparticles to knockdown COX-2 specifically in macrophages.
authors.affiliation: 2. Interdisciplinary Nanoscience Center, Department of Molecular Biology and Genetics, Aarhus University, Denmark.
authors.forename: Chuanxu
authors.initials: C
authors.lastname: Yang
authors.affiliation: 1. Department of Clinical Medicine, Aarhus University, Denmark;
authors.forename: Line
authors.initials: L
authors.lastname: Nilsson
authors.affiliation: 1. Department of Clinical Medicine, Aarhus University, Denmark;
authors.forename: Muhammad Umar
authors.initials: MU
authors.lastname: Cheema
authors.affiliation: 1. Department of Clinical Medicine, Aarhus University, Denmark;
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 1. Department of Clinical Medicine, Aarhus University, Denmark;
authors.forename: Jørgen
authors.initials: J
authors.lastname: Frøkiær
authors.affiliation: 2. Interdisciplinary Nanoscience Center, Department of Molecular Biology and Genetics, Aarhus University, Denmark.
authors.forename: Shan
authors.initials: S
authors.lastname: Gao
authors.affiliation: 2. Interdisciplinary Nanoscience Center, Department of Molecular Biology and Genetics, Aarhus University, Denmark.
authors.forename: Jørgen
authors.initials: J
authors.lastname: Kjems
authors.affiliation: 1. Department of Clinical Medicine, Aarhus University, Denmark;
authors.forename: Rikke
authors.initials: R
authors.lastname: Nørregaard
mesh_terms: D058186:Acute Kidney Injury / Q000517:prevention & control*; D000818:Animals; D002460:Cell Line; D048271:Chitosan / Q000627:therapeutic use*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006651:Histocytochemistry; D007150:Immunohistochemistry; D008264:Macrophages / Q000201:enzymology; D008297:Male; D051379:Mice; D018613:Microscopy, Confocal; D053758:Nanoparticles / Q000627:therapeutic use*; D061848:Optical Imaging; D034741:RNA, Small Interfering / Q000627:therapeutic use*; D016896:Treatment Outcome; D014517:Ureteral Obstruction / Q000150:complications*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D034741:RNA, Small Interfering; D048271:Chitosan; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2
keywords: Cyclooxygenase type 2; chitosan; mice.; siRNA; unilateral ureteral obstruction