title: Comparative effect of direct renin inhibition and AT1R blockade on glomerular filtration barrier injury in the transgenic Ren2 rat.
abstract: Renin-angiotensin system (RAS) activation contributes to kidney injury through oxidative stress. Renin is the rate-limiting step in angiotensin (ANG II) generation. Recent work suggests renin inhibition improves proteinuria comparable to ANG type 1 receptor (AT1R) blockade (ARB). Thereby, we investigated the relative impact of treatment with a renin inhibitor vs. an ARB on renal oxidative stress and associated glomerular structural and functional changes in the transgenic Ren2 rat, which manifests hypertension, albuminuria, and increased tissue RAS activity. Young Ren2 and age-matched Sprague-Dawley (SD) controls (age 6-9 wk) were treated with a renin inhibitor (aliskiren), an ARB (irbesartan), or vehicle for 21 days. Ren2 rats exhibited increases in systolic pressure (SBP), albuminuria, and renal 3-nitrotyrosine content as well as ultrastructural podocyte foot-process effacement and diminution of the podocyte-specific protein nephrin. Structural and functional alterations were accompanied by increased renal cortical ANG II, AT1R, as well as NADPH oxidase subunit (Nox2) expression compared with SD controls. Abnormalities were attenuated to a similar extent with both aliskiren and irbesartan treatment. Despite the fact the dose of irbesartan used caused a greater reduction in SBP than aliskerin treatment (P < 0.05), the effects on proteinuria, nephrin, and oxidative stress were similar between the two treatments. Our results highlight both the importance of pressor-related reductions on podocyte integrity and albuminuria as well as RAS-mediated oxidant stress largely comparable between ARB and renin inhibition treatment.
authors.affiliation: Department of Internal Medicine, University of Missouri-Columbia School of Medicine, Columbia, Missouri 65212, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Whaley-Connell
authors.forename: Ravi
authors.initials: R
authors.lastname: Nistala
authors.forename: Javad
authors.initials: J
authors.lastname: Habibi
authors.forename: Melvin R
authors.initials: MR
authors.lastname: Hayden
authors.forename: Rebecca I
authors.initials: RI
authors.lastname: Schneider
authors.forename: Megan S
authors.initials: MS
authors.lastname: Johnson
authors.forename: Roger
authors.initials: R
authors.lastname: Tilmon
authors.forename: Nathan
authors.initials: N
authors.lastname: Rehmer
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Ferrario
authors.forename: James R
authors.initials: JR
authors.lastname: Sowers
mesh_terms: D000419:Albuminuria / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000577:Amides / Q000494:pharmacology*; D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D005650:Fumarates / Q000494:pharmacology*; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000077405:Irbesartan; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology / Q000648:ultrastructure; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects* / Q000378:metabolism; D012083:Renin / Q000235:genetics / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D000804:Angiotensin II; D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; D005650:Fumarates; D000077405:Irbesartan; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D044140:Receptor, Angiotensin, Type 1; D012083:Renin; D013777:Tetrazoles; D014443:Tyrosine; D000092502:Renin Inhibitors; C473112:Ren2 protein, mouse; C113267:nephrin; C002744:3-nitrotyrosine; C446481:aliskiren; C500593:Cybb protein, rat