ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: SA-PO793

A Role of Amphiregulin in PDE3A-Mediated Renoprotection

Session Information

  • Hypertension and CVD: Mechanisms
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Hypertension and CVD

  • 1503 Hypertension and CVD: Mechanisms

Authors

  • Sholokh, Anastasiia, Max-Delbruck-Centrum fur Molekulare Medizin in der Helmholtz-Gemeinschaft, Berlin, Germany
  • Mcmurray, Brandon James, University of Toronto, Toronto, Ontario, Canada
  • Sunaga-Franze, Daniele Yumi, Max-Delbruck-Centrum fur Molekulare Medizin in der Helmholtz-Gemeinschaft, Berlin, Germany
  • Qadri, Fatimunnisa, Max-Delbruck-Centrum fur Molekulare Medizin in der Helmholtz-Gemeinschaft, Berlin, Germany
  • Zuehlke, Kerstin, Max-Delbruck-Centrum fur Molekulare Medizin in der Helmholtz-Gemeinschaft, Berlin, Germany
  • Marko, Lajos, Max Delbruck Centrum fur Molekulare Medizin Experimental and Clinical Research Center, Berlin, Berlin, Germany
  • Xu, Minze, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Patzak, Andreas, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Persson, Pontus, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Maass, Philipp G., University of Toronto, Toronto, Ontario, Canada
  • Borodina, Tatiana A., Max-Delbruck-Centrum fur Molekulare Medizin in der Helmholtz-Gemeinschaft, Berlin, Germany
  • Bähring, Sylvia, Max Delbruck Centrum fur Molekulare Medizin Experimental and Clinical Research Center, Berlin, Berlin, Germany
  • Bader, Michael, Max-Delbruck-Centrum fur Molekulare Medizin in der Helmholtz-Gemeinschaft, Berlin, Germany
  • Klussmann, Enno, Max-Delbruck-Centrum fur Molekulare Medizin in der Helmholtz-Gemeinschaft, Berlin, Germany
Background

A primary risk factor for chronic kidney disease (CKD) is hypertension. Autosomal-dominant hypertension with brachydactyly type E (HTNB) resembles essential hypertension, but the patients show almost no signs of end-organ damage such as CKD. HTNB is caused by mutations in the phosphodiesterase 3A (PDE3A) gene. Therefore, we hypothesize that HTNB-causing PDE3A-mutations are renoprotective and aim to gain insight into the underlying mechanisms.

Methods

Using CRISPR/Cas9 technology, rats expressing PDE3A with a 3 amino acid deletion (PDE3A-Δ3aa) were generated. These animals recapitulate the HTNB phenotype. Rats with a functional PDE3A knockout (Functional Del) were used as an additional control. Inner medulla (IM) and residual kidney (RK) were investigated using biochemical, molecular biological, histological, and physiological approaches. Vasa recta contractility was measured.

Results

The overall kidney morphology of the wild-type (WT), PDE3A-Δ3aa, and functional Del rats was similar. As in second-order mesenteric arteries, the media to lumen ratio of renal arteries was significantly increased in PDE3A-Δ3aa rats compared to wild-type. The relaxation of Vasa recta to forskolin was not affected in PDE3A-Δ3aa rats and appeared stronger in functional Del (both vs. WT). The mRNA and protein expression levels of proinflammatory cytokines and fibrosis markers remained at similar levels as in wild-type rats in both IM and RK. However, compared to wild-type animals, collagen levels in IM and RK of PDE3A-Δ3aa and in IM of functional Del rats were significantly increased. Amphiregulin (AREG) is a fibrosis- and thus kidney damage-inducing epidermal growth factor receptor (EGFR) agonist. The mRNA and protein expression levels of AREG were significantly decreased in IM of PDE3A-Δ3aa animals compared to wild-type, while its serum level remained unchanged.

Conclusion

Our data reveal that PDE3A mutations protect the kidneys from hypertension-induced damage and suggested that AREG plays a role in the underlying mechanisms.

Funding

  • Government Support – Non-U.S.