title: Aliskiren attenuates proteinuria in mice with lupus nephritis by a blood pressure-independent mechanism.
abstract: This study revealed that low-dose aliskiren treatment could attenuate proteinuria by interrupting the renin-angiotensin system in mice with lupus nephritis, and the beneficial effect was beyond blood pressure control. An in and ex vivo fluorescence imaging (using a non-invasion in vivo imaging system) showed intense labeling of renin in the kidneys of female MRL/lpr mice. In the study, Alzet mini-osmotic pumps were implanted into 6-week-old female MRL/lpr mice. Pumps were filled with either phosphate-buffered saline or a solution of aliskiren dissolved in phosphate-buffered saline (20 mg/kg/day) and replaced at 28-day intervals. Mice were sacrificed at four and eight weeks. To label cells for DNA synthesis, bromodeoxyuridine (BrdU) (50 mg/kg) was injected intraperitoneally an hour prior to sacrifice. The level of renin inhibition was adequate, as aliskiren-treated mice demonstrated higher renal renin mRNA expression than controls (p < 0.05). Although there were no significant differences in the systolic blood pressure (control versus aliskiren-treated: 127.20 ± 4.44 mmHg versus 103.80 ± 7.40 mmHg, p > 0.05) and heart rate (control versus aliskiren-treated: 680.50 ± 11.71 versus 647.80 ± 13.90, p > 0.05) of both groups after eight weeks, there was significant reduction of inflammatory cytokines (transforming growth factor-beta1, regulated on activation normal T cell expressed, monocyte chemoattractant protein-1 and osteopontin, p < 0.05), reduction of innate immunity (toll-like receptor 7, p < 0.05), as well as a reduction of glomerular proliferation and inflammation (BrdU-, CD45-, CD3- and F4/80-positive glomerular cells, p < 0.01) after aliskiren infusion, which might translate into an improvement in proteinuria (control versus aliskiren-treated: 493.7 versus 843.7 mg/g, p < 0.01) or weight gain (control versus aliskiren-treated: 5.65 ± 1.61 versus 8.67 ± 0.97%, p < 0.05).
authors.affiliation: Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, 199 Tung Hwa North Rd., Taipei, Taiwan. m19570@adm.cgmh.org.tw
authors.forename: T-H
authors.initials: TH
authors.lastname: Yen
authors.forename: H-Y
authors.initials: HY
authors.lastname: Yang
authors.forename: Y-H
authors.initials: YH
authors.lastname: Yeh
authors.forename: P-H
authors.initials: PH
authors.lastname: Chu
authors.forename: C-J
authors.initials: CJ
authors.lastname: Wen
authors.forename: J-F
authors.initials: JF
authors.lastname: Fu
authors.forename: I-K
authors.initials: IK
authors.lastname: Wang
authors.forename: C-C
authors.initials: CC
authors.lastname: Liang
authors.forename: C-T
authors.initials: CT
authors.lastname: Chang
authors.forename: K-H
authors.initials: KH
authors.lastname: Chen
authors.forename: Y-C
authors.initials: YC
authors.lastname: Tian
authors.forename: C-C
authors.initials: CC
authors.lastname: Hung
authors.forename: J-L
authors.initials: JL
authors.lastname: Lin
authors.forename: C-W
authors.initials: CW
authors.lastname: Yang
mesh_terms: D000577:Amides / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D005650:Fumarates / Q000494:pharmacology / Q000627:therapeutic use*; D008181:Lupus Nephritis / Q000150:complications / Q000188:drug therapy*; D051379:Mice; D008815:Mice, Inbred Strains; D011507:Proteinuria / Q000188:drug therapy* / Q000209:etiology; D012076:Renal Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D005650:Fumarates; D012076:Renal Agents; D000092502:Renin Inhibitors; C446481:aliskiren