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Abstract: TH-OR087

Functional Intrarenal Alterations and Morphological Glomerular Basement Changes in Mice Deficient of the Angiotensinase Aminopeptidase A

Session Information

Category: Glomerular Diseases

  • 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

  • Marahrens, Benedikt, Northwestern University Feinberg Medical School, Chicago, United States
  • Schulze, Arndt, Northwestern University Feinberg Medical School, Chicago, United States
  • Wysocki, Jan, Northwestern University Feinberg Medical School, Chicago, Illinois, United States
  • Ye, Minghao, Northwestern University Feinberg Medical School, Chicago, Illinois, United States
  • Kanwar, Yashpal S., Northwestern University Feinberg Medical School, Chicago, Illinois, United States
  • Velez, Juan Carlos Q., Ochsner Clinic Foundation, New Orleans, Louisiana, United States
  • Batlle, Daniel, Northwestern University Feinberg Medical School, Chicago, Illinois, United States
Background

Aminopeptidase A (APA) is an enzyme abundantly expressed in the kidney glomeruli and tubules which degrades both Angiotensin (Ang) I and Ang II and thereby potentially important for downregulating renal RAS overactivity. Our objective was to examine whether there is a kidney phenotype associated with APA deficiency.

Methods

Urinary albumin excretion rate (AER) and glomerular filtration rate (GFR) were evaluated in BALB/c mice with global APA deficiency (APA-/-) and compared to wild-type (WT) mice. Kidneys harvested from 8-month-old mice were examined by light microscopy (LM) and electron microscopy (EM). Abundance of endogenous kidney Ang II and the ability of the kidneys to degrade exogenous Ang II ex vivo were evaluated. In addition, kidney Ang-converting enzyme (ACE) expression and activity were measured.

Results

APA-/- mice had normal urinary AER and a GFR similar to that of wild-type (WT) littermates. By LM, kidneys from APA-/- mice showed mild mesangial expansion and mild to moderate thickening of the glomerular basement membrane (GBM). By EM, the APA-/- also exhibited mild increase of the mesangial matrix and moderate thickening of the GBM with a striking appearance of knob-like structures and sub-endothelial expansion. Kidney lysates of APA-/- showed a markedly slower degradation of exogenous Ang II (10 µM) compared to those of WT as shown by residual Ang II levels after 30 minutes (48.6 ± 4 vs 16.0 ± 5 %, respectively, p<0.001). Endogenous Ang II levels in APA-/-, however, were not different compared to WT kidneys (1.04 ± 0.2 vs 0.89 ± 0.3, fmol/mg, p=ns). In addition, kidney lysates of APA-/- mice showed a profound decrease in ACE activity (2981 ± 374 vs 10021 ± 897 rfu/µg, respectively, p<0.001), mRNA (RT-real time PCR) and protein (Western blot) levels. The downregulation of ACE by decreasing Ang II formation likely counterbalances the impaired Ang II degradation due to APA deficiency.

Conclusion

Deficiency of APA results in glomerular morphological alterations in the mesangial stalk and the GBM and functional adaptations in intrarenal ACE expression and activity. These findings support a role of APA in maintenance of glomerular structure and intrarenal Ang homeostasis.

Funding

  • NIDDK Support