Abstract: FR-PO198

Activin Receptor Activation in the Skeleton, Vasculature, Heart, and Kidney During CKD

Session Information

Category: Hypertension

  • 1103 Vascular Biology and Dysfunction

Authors

  • Sugatani, Toshifumi, WASHINGTON UNIVERSITY IN ST. LOUIS SCHOOL OF MEDIC, St.Louis, Missouri, United States
  • Williams, Matthew James, None, Saint Louis, Missouri, United States
  • Agapova, Olga A., Washington University School of Medicine, St. Louis, Missouri, United States
  • Malluche, Hartmut H., University of Kentucky, Lexington, Kentucky, United States
  • Hruska, Keith A., Washington University St. Louis, St. Louis, Missouri, United States
Background

To study whether factors stimulating renal fibrosis produce systemic disease, we examined activin receptor type IIA (ActRIIA) activation in CKD by signal analysis and inhibition in Alport syndrome mice, using a ActRIIA ligand trap (RAP-011) from 75 to 200 days of life.

Methods

We measured ActRIIA signaling and inhibited its activity with RAP-011.

Results

By 200 days, Alport mice had severe CKD and the CKD-MBD, consisting of osteodystrophy, vascular calcification, cardiac hypertrophy, hyperphosphatemia, hyperparathyroidism, and elevated FGF23 and reduced klotho levels.ActRIIA inhibition by RAP-011 reversed CKD-stimulated bone resorption and osteoblast dysfunction by inhibition of osteoclast function, while osteoblast function and bone formation were increased. ActRIIA inhibition prevented formation of calcium apatite deposits in aortic adventitia and tunica media and decreased aortic Ca levels from 0.59 mg/g in Alport mice to 0.36 in RAP-011 treated mice (p<.05). Aortic ActRIIA stimulation increased p-Smad2 levels and the transcriptional targets, sm22α and αSMA, in Alport mice. ActRIIA inhibition reversed aortic expression of Runx2 and osterix, markers of osteoblastic transition. Heart weight was 26% increased in Alport mice, but remained normal during RAP-011 treatment (p<.01). In 150 do Alport mice, GFR was reduced by 55%, p<0.05, but GFR was only 30% reduced in the RAP-011 treated group. At 200 do, the BUN was 100mg/dl in Alport mice compared to 60 in the treated group. In kidneys of 200 day old Alport mice, ActRIIA and p-Smad2 were induced and MCP-1, fibronectin and interstitial fibrosis were stimulated, but inhibited by RAP-011 treatment.

Conclusion

The results demonstrate CKD activation of ActRIIA signaling contributing to CKD-MBD components, osteodystrophy and cardiovascular disease, and to renal fibrosis. Inhibition of ActRIIA signaling may be efficacious in Alport syndrome.

Funding

  • NIDDK Support