Abstract: PO1828
Nephroprotective Effects of PDE3A Gene Mutations
Session Information
- Hypertension and CVD: Mechanisms
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Hypertension and CVD
- 1403 Hypertension and CVD: Mechanisms
Authors
- Sholokh, Anastasiia, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- Borodina, Tatiana A., Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- Sunaga-Franze, Daniele Yumi, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- Zuehlke, Kerstin, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- Bähring, Sylvia, Charite, Experimental and Clinical Research Center, Berlin, Germany
- Bader, Michael, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- Klussmann, Enno, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
Group or Team Name
- Anchored Signalling
Background
Chronic kidney disease (CKD) affects more than 700 million people worldwide. The molecular mechanisms of CKD are poorly understood and the treatment approaches are non-causal and therefore non-selective. Mutations in the gene coding for phosphodiesterase 3A (PDE3A) cause autosomal-dominant hypertension with brachydactyly type E (HTNB). Despite HTNB patients have decade-long hypertension, their kidneys hardly display any hypertension-induced damage. We hypothesize, understanding how PDE3A mutations protect from CKD development will help to uncover the molecular mechanisms of CKD and pave the way to new strategies for CKD prevention and treatment
Methods
CRISPR/Cas9 was applied to introduce mutations in a regulatory or the catalytic domain encoding segment of the Pde3a gene of rats to recapitulate the HTNB phenotype (confirmed by radio-telemetry measurements). The inner medulla (IM) and residual kidney (RK) were subjected to Western blot analysis and RNA-sequencing with subsequent validation of the most promising genes-candidates.
Results
In wild-type animals, PDE3A mRNA and protein expression were higher in the IM compared to the RK. In PDE3A mutant animals, the IM PDE3A protein level was decreased. Protein levels of various cAMP signalling pathway components were not changed in PDE3A mutants in both IM and RK. However, the phosphorylation level of cAMP response element-binding protein (CREB) was significantly increased in IM in PDE3A mutants. The mRNA levels of 27 genes were changed upon PDE3A mutation in the regulatory region; some of them clustered as mitochondrial or inflammatory response proteins. The PDE3A mutation in the catalytic domain led to more profound changes in mRNA expression profiles.
Conclusion
In summary, our data show that hypertension-inducing mutations of PDE3A have no profound effects on the expression level of cAMP signaling proteins but change the global transcriptional profiles in the kidney. Alterations of the inflammatory cytokine production or mitochondrial metabolism could be involved in the renoprotective effects of PDE3A mutations.
Funding
- Government Support – Non-U.S.