Abstract: FR-PO715

Mice Deficient in Aminopeptidase A Have Augmented Albuminuria Following Renal Mass Reduction

Session Information

Category: Glomerular

  • 1002 Glomerular: Basic/Experimental Pathology

Authors

  • Fitzgibbon, Wayne R., Medical University of South Carolina, Charleston, South Carolina, United States
  • Arif, Ehtesham, Medical University of South Carolina, Charleston, South Carolina, United States
  • Deng, Peifeng, Medical University of South Carolina, Charleston, South Carolina, United States
  • Xiao, Fengxia, Ottawa Hospital Research Institute, Ottawa, Alberta, Canada
  • Burger, Dylan, Kidney Research Centre, Ottawa, Ontario, Canada
  • Janech, Michael G., Medical University of South Carolina, Charleston, South Carolina, United States
  • Nihalani, Deepak, Medical University of South Carolina, Charleston, South Carolina, United States
  • Velez, Juan Carlos Q., Ochsner Clinic Foundation, New Orleans, Louisiana, United States
Background


Aminopeptidase A (APA) is a membrane-bound metalloproteinase expressed in podocytes and tubular epithelia. We have previously shown that global deficiency in APA increases susceptibility to acute immune- or Ang-dependent glomerular injury. We hypothesized that APA acts to minimize podocyte damage during progressive chronic kidney disease.

Methods

To test this hypothesis we measured urine flow rate, urine albumin (Alb), creatinine (Cr), and microparticle (MP) levels in 129Sv/C57Bl6 wild type (WT, n=6) and APA KO (n=6) mice subjected to remnant nephropathy. Twenty-four hour (24h) urine collections were obtained prior to, and 2 and 4 weeks following 5/6 reduction in renal mass.

Results

Baseline values were not different between the two strains. Renal mass reduction induced albuminuria in both groups at 2 weeks; however, 24h albumin excretion (UAlbV) was markedly higher for the KO compared to the WT mice at both 2 weeks (p<0.001) and 4 weeks (p<0.001). UAlbV was 11 (6–21), 161 (57–497) and 169 (42–1230) µg/24h, and 17 (6–43), 1554 (712–2217) and 1400 (629–2882) µg/24h for baseline, 2 and 4 week periods for the WT and the APAKO mice, respectively. Similar findings were observed when albumin levels were expressed as albumin/creatinine ratio (UACR). UACRs were 277 (113–743) vs 1856 (842–2539) at 2 weeks (p<0.001) and 242 (116–1781) vs 1837 (618–3845) at 4 weeks (p<0.001) for the WT and APAKO respectively. Concomitant with the reduction in renal mass was a decrease in the generation of total urinary MP (uMP/Cr) that was similar in both groups. Further, the formation of podocyte-derived podoplanin-stained (ps) MP also decreased in both groups. For WT, the generation of psMP at baseline and 2 weeks was 2.2x106 ± 1.0x106 vs 4.8x105 ± 9.2x105 psMP/mg (p=0.03) and at 4 weeks 2.6x105 ± 1.4x105 psMP/mg (p<0.01). For the APAKO mice psMP at baseline and 2 weeks was 2.2x106 ± 1.2x106 vs 4.3x104 ± 4.1x104 psMP/mg (p<0.01) and at 4 weeks 1.7x105 ± 2.4x105 psMP/mg (p<0.01).

Conclusion

Our findings support a role for APA in ameliorating glomerular injury following 5/6 renal ablation. The finding that the formation of (ps)MP was not different between the 2 groups 2 weeks after renal injury, suggests that the chronic renoprotective role of APA may not be associated with attenuation of podocyte MP formation.

Funding

  • Private Foundation Support