Kidney Week

Abstract: TH-PO1122

Gain-of-Function Mutation in PDE3A Limits Renal Signs of CKD

Session Information

• CKD: Mechanisms - 1
  October 24, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2303 CKD (Non-Dialysis): Mechanisms

Authors

• Potapenko, Olena, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany

Olena Potapenko, MSc

• Bartolomaeus, Theda Ulrike Particia, Max-Delbruck-Centrum fur Molekulare Medizin in der Helmholtz-Gemeinschaft, Buch, Berlin, Germany

Theda Ulrike Particia Bartolomaeus, MS, MSc

• Spindler, Fiona, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany

Fiona Spindler

• Bader, Michael, Max-Delbruck-Centrum fur Molekulare Medizin in der Helmholtz-Gemeinschaft, Buch, Berlin, Germany

Michael Bader

• Sholokh, Anastasiia, Max-Delbruck-Centrum fur Molekulare Medizin in der Helmholtz-Gemeinschaft, Buch, Berlin, Germany

Anastasiia Sholokh, MS

• Langanki, Reika, Max-Delbruck-Centrum fur Molekulare Medizin in der Helmholtz-Gemeinschaft, Buch, Berlin, Germany

Reika Langanki

• Vila, Eremire, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany

Eremire Vila

• Forslund, Sofia Kirke, Max-Delbruck-Centrum fur Molekulare Medizin in der Helmholtz-Gemeinschaft, Buch, Berlin, Germany

Sofia Kirke Forslund, PhD

• Klussmann, Enno, Max-Delbruck-Centrum fur Molekulare Medizin in der Helmholtz-Gemeinschaft, Buch, Berlin, Germany

Enno Klussmann, PhD

• Marko, Lajos, Max-Delbruck-Centrum fur Molekulare Medizin in der Helmholtz-Gemeinschaft, Buch, Berlin, Germany

Lajos Marko, MD, PhD

Background

Hypertension is a major risk factor for the development of chronic kidney disease (CKD). Hypertension and brachydactyly syndrome is caused by gain of function mutations in the phosphodiesterase 3a (PDE3A) gene and leads – if untreated – to stroke and premature death. However, patients hardly develop end-organ damage. Here, we investigated the effect of the PDE3A gene mutations on renal manifestation in a rat model of CKD.

Methods

PDE3A-activating (Δ3aa), litter-mate wild-type (WT) and PDE3A-deleted (functional DEL) rats were generated and CKD was induced by bilateral renal ischemia through clamping renal arteries for 45 minutes. Four weeks after surgery kidneys were harvested for histological and gene expression analyses. Blood pressure was continuously measured by telemetry for 1 week before and 3 weeks after renal ischemia.

Results

Serum creatinine and cystatin C levels were elevated 4 weeks after CKD induction in all 3 groups of rats which underwent CKD-inducing surgery in comparison to values before surgery or values of sham-operated animals. However, no difference could be observed between the groups. Δ3aa rats had significantly higher, and functional DEL significantly lower systolic blood pressure than WT rats (142 vs 121 and 115 mmHg, respectively) which was not affected by the CKD induction. CKD induction led to a reduction of the area of the Bowman's capsule (p<0.05) and the glomerular capsule area (p=0.0536) in WT but not in the Δ3aa rats. CKD induction led to increased media-to lumen ratio of renal arteries in WT rats but not in Δ3aa rats. Additionally, induction of CKD led to significant renal fibrosis in the kidneys of both WT and Δ3aa rats. However, the fibrotic area in kidneys of Δ3aa rats was less than that of the WT rats. The expression of genes involved in fibrosis showed similar trends in WT and Δ3aa rats.

Conclusion

Our data show that gain-of-function mutation of PDE3A limit the development of CKD-induced renal changes arguing that PDE3A modulation can be a useful approach for prevention of hypertension-associated CKD.

Funding

• Government Support – Non-U.S.