title: Deficiency of the Angiotensinase Aminopeptidase A Increases Susceptibility to Glomerular Injury.
abstract: Aminopeptidase A (APA) is expressed in glomerular podocytes and tubular epithelia and metabolizes angiotensin II (AngII), a peptide known to promote glomerulosclerosis. In this study, we tested whether APA expression changes in response to progressive nephron loss or whether APA exerts a protective role against glomerular damage and during AngII-mediated hypertensive kidney injury. At advanced stages of FSGS, fawn-hooded hypertensive rat kidneys exhibited distinctly increased APA staining in areas of intact glomerular capillary loops. Moreover, BALB/c APA-knockout (KO) mice injected with a nephrotoxic serum showed persistent glomerular hyalinosis and albuminuria 96 hours after injection, whereas wild-type controls achieved virtually full recovery. We then tested the effect of 4-week infusion of AngII (400 ng/kg per minute) in APA-KO and wild-type mice. Although we observed no significant difference in achieved systolic BP, AngII-treated APA-KO mice developed a significant rise in albuminuria not observed in AngII-treated wild-type mice along with increased segmental and global sclerosis and/or collapse of juxtamedullary glomeruli, microcystic tubular dilation, and tubulointerstitial fibrosis. In parallel, AngII treatment significantly increased the kidney AngII content and attenuated the expression of podocyte nephrin in APA-KO mice but not in wild-type controls. These data show that deficiency of APA increases susceptibility to glomerular injury in BALB/c mice. The augmented AngII-mediated kidney injury observed in association with increased intrarenal AngII accumulation in the absence of APA suggests a protective metabolizing role of APA in AngII-mediated glomerular diseases.
authors.affiliation: Department of Nephrology, Ochsner Clinic Foundation, New Orleans, Louisiana; juancarlos.velez@ochsner.org.
authors.forename: Juan Carlos Q
authors.initials: JCQ
authors.lastname: Velez
authors.affiliation: Division of Nephrology, Department of Medicine and.
authors.forename: Ehtesham
authors.initials: E
authors.lastname: Arif
authors.affiliation: Division of Nephrology, Department of Medicine and.
authors.forename: Jessalyn
authors.initials: J
authors.lastname: Rodgers
authors.affiliation: Institute of Public and Preventative Health, Augusta University, Augusta, Georgia; and.
authors.forename: Megan P
authors.initials: MP
authors.lastname: Hicks
authors.affiliation: Division of Nephrology, Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: John M
authors.initials: JM
authors.lastname: Arthur
authors.affiliation: Division of Nephrology, Department of Medicine and.
authors.forename: Deepak
authors.initials: D
authors.lastname: Nihalani
authors.affiliation: Departments of Pathology and.
authors.forename: Evelyn T
authors.initials: ET
authors.lastname: Bruner
authors.affiliation: Division of Nephrology, Department of Medicine and.
authors.forename: Milos N
authors.initials: MN
authors.lastname: Budisavljevic
authors.affiliation: Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Carl
authors.initials: C
authors.lastname: Atkinson
authors.affiliation: Division of Nephrology, Department of Medicine and.
authors.forename: Wayne R
authors.initials: WR
authors.lastname: Fitzgibbon
authors.affiliation: Division of Nephrology, Department of Medicine and.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Janech
mesh_terms: D000818:Animals; D004198:Disease Susceptibility; D043384:Glutamyl Aminopeptidase / Q000172:deficiency*; D007674:Kidney Diseases / Q000201:enzymology* / Q000209:etiology*; D007678:Kidney Glomerulus; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051381:Rats
chemical_list: D043384:Glutamyl Aminopeptidase
keywords: albuminuria; angiotensin II; glomerulosclerosis; intrarenal; murine; podocyte