Deficiency of the Angiotensinase Aminopeptidase A Increases Susceptibility to Glomerular Injury

J Am Soc Nephrol. 2017 Jul;28(7):2119-2132. doi: 10.1681/ASN.2016111166. Epub 2017 Feb 15.


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.

Keywords: albuminuria; angiotensin II; glomerulosclerosis; intrarenal; murine; podocyte.

MeSH terms

  • Animals
  • Disease Susceptibility
  • Glutamyl Aminopeptidase / deficiency*
  • Kidney Diseases / enzymology*
  • Kidney Diseases / etiology*
  • Kidney Glomerulus*
  • Male
  • Mice
  • Mice, Knockout
  • Rats


  • Glutamyl Aminopeptidase