Knockout of aminopeptidase A in mice causes functional alterations and morphological glomerular basement membrane changes in the kidneys.

Benedikt Marahrens, Arndt Schulze, Jan Wysocki, Meei-Hua Lin, Minghao Ye, Yashpal S Kanwar, Michael Bader, Juan Carlos Q Velez, Jeffrey H Miner, Daniel Batlle

Kidney international 2021 Apr

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Aminopeptidase A is one of the most potent enzymes within the renin-angiotensin system in terms of angiotensin II degradation. Here, we examined whether there is a kidney phenotype and any compensatory changes in other renin angiotensin system enzymes involved in the metabolism of angiotensin II associated with aminopeptidase A deficiency. Kidneys harvested from aminopeptidase A knockout mice were examined by light and electron microscopy, immunohistochemistry and immunofluorescence. Kidney angiotensin II levels and the ability of renin angiotensin system enzymes in the glomerulus to degrade angiotensin II ex vivo, their activities, protein and mRNA levels in kidney lysates were evaluated. Knockout mice had increased blood pressure and mild glomerular mesangial expansion without significant albuminuria. By electron microscopy, knockout mice exhibited a mild increase of the mesangial matrix, moderate thickening of the glomerular basement membrane but a striking appearance of knob-like structures. These knobs were seen in both male and female mice and persisted after the treatment of hypertension. In isolated glomeruli from knockout mice, the level of angiotensin II was more than three-fold higher as compared to wild type control mice. In kidney lysates from knockout mice angiotensin converting enzyme activity, protein and mRNA levels were markedly decreased possibly as a compensatory mechanism to reduce angiotensin II formation. Thus, our findings support a role for aminopeptidase A in the maintenance of glomerular structure and intra-kidney homeostasis of angiotensin peptides. Copyright © 2021. Published by Elsevier Inc.

Citation

Benedikt Marahrens, Arndt Schulze, Jan Wysocki, Meei-Hua Lin, Minghao Ye, Yashpal S Kanwar, Michael Bader, Juan Carlos Q Velez, Jeffrey H Miner, Daniel Batlle. Knockout of aminopeptidase A in mice causes functional alterations and morphological glomerular basement membrane changes in the kidneys. Kidney international. 2021 Apr;99(4):900-913