Abstract: FR-PO994
Renoprotective Effect of Phosphodiesterase (PDE) 3A Mutations in a Rat Model of CKD
Session Information
- CKD: Pathobiology - I
November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2203 CKD (Non-Dialysis): Mechanisms
Authors
- Bartolomaeus, Theda Ulrike Particia, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
- Langanki, Reika, Max-Delbruck-Centrum fur Molekulare Medizin in der Helmholtz-Gemeinschaft, Berlin-Buch, Berlin, Germany
- Potapenko, Olena, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
- Sholokh, Anastasiia, Max-Delbruck-Centrum fur Molekulare Medizin in der Helmholtz-Gemeinschaft, Berlin-Buch, Berlin, Germany
- Zuehlke, Kerstin, Max-Delbruck-Centrum fur Molekulare Medizin in der Helmholtz-Gemeinschaft, Berlin-Buch, Berlin, Germany
- Bähring, Sylvia, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
- Bader, Michael, Max-Delbruck-Centrum fur Molekulare Medizin in der Helmholtz-Gemeinschaft, Berlin-Buch, Berlin, Germany
- Forslund, Sofia Kirke, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
- Marko, Lajos, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
- Klussmann, Enno, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
Background
Hypertension is associated with chronic kidney disease (CKD) in more than 80% of cases. Along with diabetes, hypertension is considered as a major risk factor. Here, we are studying a Mendelian form of hypertension (HTNB) that is associated with activating mutations in the PDE3A gene. Without treatment, mutation leads to premature death caused by stroke, but remarkably patients are free from impaired kidney function and other forms of target-organ damage. Here, we tested PDE3A as a target for renoprotection against CKD.
Methods
PDE3A-activating (d3aa), PDE3A-deleted (functional DEL), and litter-mate wild-type (WT) rat strains were generated and CKD was induced by bilateral renal ischemia by clamping renal artery for 45 minutes. Blood pressure was continuously measured by telemetry 2 weeks before and 4 weeks after renal ischemia. Renal function was assessed before, 24 hours and 4 weeks after CKD induction. After 4 weeks, kidneys were harvested for further analysis.
Results
Serum creatinine was significantly elevated 4 weeks after CKD induction (baseline 0.33, 0.31 and 0.34 mg/dL vs. 0.48, 0.49 and 0.38 mg/dL at 4 weeks, in d3aa, WT and functional DEL, respectively). Rats with PDE3A-activating mutation had significantly higher systolic blood pressure than WT or functional DEL animals (142 vs 121 and 115 mmHg, respectively). Despite high blood pressure, d3aa animals had similar serum creatinine, blood urea nitrogen and cystatin-C levels before, 24 hours after and 4 weeks after bilateral renal ischemia. The same was true for gene expression of renal damage markers lipocalin-2 (Ngal) and kidney injury molecule-1 and fibrosis markers collagen 1 or fibronectin. Western blot and histology confirmed gene expression data.
Conclusion
Our data argue that PDE3A modulation can be a useful approach in hypertension associated CKD.
Funding
- Government Support – Non-U.S.