title: Antisense-mediated angiotensinogen inhibition slows polycystic kidney disease in mice with a targeted mutation in Pkd2.
abstract: Renal cyst enlargement is associated with the activation of both the circulating and intrarenal renin-angiotensin systems. Angiotensinogen (AGT) is the substrate for renin. The aim of the present study was to determine the effect of AGT inhibition on renal cyst enlargement. An AGT antisense oligonucleotide (ASO) that selectively inhibits AGT mRNA was injected once weekly in PKD2WS25 mice [an orthologous model of human autosmal dominant polycystic kidney disease (PKD) involving mutation of the Pkd2 gene] from 4 to 16 wk of age. The AGT ASO resulted in a 40% decrease in AGT RNA in the kidney, a 60% decrease in AGT RNA in the liver, and a significant decrease in AGT protein in the kidney and serum. The AGT ASO resulted in a significant decrease in kidney size, cyst volume density, and blood urea nitrogen. The AGT ASO resulted in a significant decrease in transforming growth factor-β and interstitial fibrosis in the kidney. Mice treated with the AGT ASO had a significant decrease in proinflammatory cytokines [chemokine (C-X-C motif) ligand (CXCL)1 and IL-12] in the kidney. Cluster of differentiation (CD)36 is a scavenger receptor found on tubular cells that can activate the renin-angiotensin system. Administration of a CD36 ASO had no effect on PKD and kidney function, suggesting that the effect of the AGT ASO is independent of CD36. In summary, AGT inhibition resulted in significant decreases in kidney size and cyst volume and an improvement in kidney function in PKD mice. The AGT ASO resulted in a decrease in transforming growth factor-β, interstitial fibrosis, and the proinflammatory cytokines CXCL1 and IL-12 in the kidney.
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado at Denver, Aurora, Colorado; and.
authors.forename: Kameswaran
authors.initials: K
authors.lastname: Ravichandran
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado at Denver, Aurora, Colorado; and.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Ozkok
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado at Denver, Aurora, Colorado; and.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: ISIS Pharmaceuticals, Carlsbad, California.
authors.forename: Adam E
authors.initials: AE
authors.lastname: Mullick
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado at Denver, Aurora, Colorado; and Charles.edelstein@ucdenver.edu.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Edelstein
mesh_terms: D000808:Angiotensinogen / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001806:Blood Urea Nitrogen; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D005355:Fibrosis; D015316:Genetic Therapy / Q000379:methods*; D018664:Interleukin-12 / Q000378:metabolism; D007668:Kidney / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage*; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D012333:RNA, Messenger / Q000378:metabolism; D020127:Recovery of Function; D050396:TRPP Cation Channels / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000808:Angiotensinogen; D018955:CD36 Antigens; D054360:Chemokine CXCL1; D018664:Interleukin-12; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D050396:TRPP Cation Channels; D016212:Transforming Growth Factor beta; C534932:Agt protein, mouse; C475895:Cxcl1 protein, mouse
keywords: angiotensinogen; cytokines; fibrosis; polycystic kidney; polycystic kidney disease; renin-angiotensin system