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Atp6ap2 ablation in adult mice impairs viability through multiple organ deficiencies
Olivia Wendling1, Marie-France Champy1, Solène Jaubert2
1CELPHEDIA-PHENOMIN, Institut Clinique de la Souris (ICS), CNRS, INSERM, University of Strasbourg, 1 rue Laurent Fries, F-67404, Illkirch-Graffenstaden, France.
Abstract:
ATP6AP2 codes for the (pro)renin receptor and is an essential component of vacuolar H+ ATPase. Activating (pro)renin for conversion of Angiotensinogen to Angiotensin makes ATP6AP2 attractive for drug intervention. Tissue-specific ATP6AP2 inactivation in mouse suggested a strong impact on various organs. Consistent with this, we found that embryonic ablation of Atp6ap2 resulted in both male hemizygous lethality and female haploinsufficiency. Next, we examined the phenotype of an induced inactivation in the adult animal, most akin to detect potential effect of functional interference of ATP6AP2 through drug therapy. Induced ablation of Atp6ap2, even without equal efficiency in all tissues (aorta, brain and kidney), resulted in rapid lethality marked by weight loss, changes in nutritional as well as blood parameters, leukocyte depletion, and bone marrow hypoplasia. Upon Atp6ap2 ablation, the colon demonstrated a rapid disruption of crypt morphology, aberrant proliferation, cell-death activation, as well as generation of microadenomas. Consequently, disruption of ATP6AP2 is extremely poorly tolerated in the adult, and severely affects various organ systems demonstrating that ATP6AP2 is an essential gene implicated in basic cellular mechanisms and necessary for multiple organ function. Accordingly, any potential drug targeting of this gene product must be strictly assessed for safety.
Insights
The (pro)renin receptor gene, ATP6AP2, is vital for multiple organ functions. Its disruption in adult mice led to rapid lethality, highlighting the need for safety assessments in drug development targeting ATP6AP2.
Area of Science:
- Molecular Biology
- Genetics
- Physiology
Background:
- ATP6AP2 encodes the (pro)renin receptor, a key component of vacuolar H+ ATPase.
- The (pro)renin receptor's role in activating (pro)renin for angiotensin conversion makes it a potential drug target.
Purpose of the Study:
- To investigate the in vivo effects of ATP6AP2 disruption in adult mice.
- To assess the impact of ATP6AP2 functional interference on various organ systems.
Main Methods:
- Induced inactivation of the Atp6ap2 gene in adult mice.
- Phenotypic analysis including organ-specific effects, weight, blood parameters, and bone marrow evaluation.
- Histological examination of colon morphology and cell proliferation.
Main Results:
- Embryonic ablation of Atp6ap2 caused male hemizygous lethality and female haploinsufficiency.
- Induced adult Atp6ap2 ablation resulted in rapid lethality, weight loss, altered blood and nutritional parameters, leukocyte depletion, and bone marrow hypoplasia.
- Colon disruption included crypt morphology changes, aberrant proliferation, cell death, and microadenoma formation.
Conclusions:
- ATP6AP2 is essential for multiple organ functions and basic cellular mechanisms in adult mammals.
- Disruption of ATP6AP2 is poorly tolerated, leading to severe multi-organ effects and lethality.
- Drug targeting of ATP6AP2 requires rigorous safety evaluations due to its critical role.
