Abstract: PO1704
Mice Deficient in Aminopeptidase A Have Worse Glomerular Injury in Response to Chronic Renal Mass Reduction
Session Information
- Podocyte Pathobiology: Basic Science Studies and Animal Models
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1204 Podocyte Biology
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
- Lipschutz, Joshua H., Medical University of South Carolina, Charleston, South Carolina, United States
- Okabayashi, Yusuke, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Puelles, Victor G., Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Wysocki, Jan, Northwestern University, Evanston, Illinois, United States
- Batlle, Daniel, Northwestern University, Evanston, Illinois, United States
- Velez, Juan Carlos Q., The University of Queensland Ochsner Clinical School New Orleans, New Orleans, Louisiana, United States
Background
Aminopeptidase A (APA) is a membrane-bound metalloproteinase expressed in podocytes and tubular epithelia. It is a key enzyme in metabolizing angiotensin (Ang) II and diverting Ang I from the formation of Ang II. A recent finding suggests that APA also plays a role in the maintenance of glomerular structure. We have previously shown that global deficiency in APA augmented albuminuria in the early phase of remnant nephropathy. We sought to determine the effect of APA deficiency in a later phase of remnant nephropathy.
Methods
We measured urinary albumin (Alb) and creatinine (Cr) excretion, podocyte morphology and kidney histopathology in 129Sv/C57Bl6 wild type (WT, n=6) and APAKO mice (n=6) subjected to renal mass reduction. Twenty-four hour (24h) urine collections were obtained prior to, and then 2, 4, 6 and 8 weeks following 5/6 nephrectomy. Podocyte density was assessed by immunofluorescence utilizing synaptopodin and Dachshund Family Transcription Factor 1 as podocyte markers.
Results
Baseline median UAlbV was 15 (13-24) and 16 (11-46) µg/24 for the WT and APA mice respectively. Renal mass reduction induced albuminuria in both groups at 2 weeks. However, 24h albumin excretion (UAlbV) was markedly higher for the APAKO compared to the WT mice at all time points post 5/6 nephrectomy (p = 0.0035). Median UAlbV at 8 weeks was 104 (33-536) and 1556 (1154-3890) µg/24 (p=0.0159) for the WT and APAKO mice. Similar findings were observed when albumin levels were expressed as urine Alb/Cr. The percentage of glomeruli with segmental or global hyalinosis/sclerosis was greater for APAKO mice compared to the WT (36% vs. 4%, p<0.01). Further, APAKO mice had a higher level of glomerular collapse (32% vs. 2%, p<0.005), parietal epithelial hyperplasia (pseudo-crescents) (28% vs. 2%, p<0.01), and a greater degree of tubular injury and microcystic tubular dilatation (45% vs. 5%, p<0.01). Affected glomeruli from APAKO mice showed a marked decrease in podocyte number (p<0.01). Among glomeruli with preserved architecture, podocyte size was reduced in APAKO mice (p<0.001). Neither BUN nor plasma Ang II levels were different between the 2 groups at 8 weeks.
Conclusion
Our findings further support a role for APA in attenuating glomerular injury following 5/6 renal ablation.
Funding
- Private Foundation Support