Receptor Activation Promotes Kidney Disease Development in Mice with Alport Syndrome, Study Shows

Receptor Activation Promotes Kidney Disease Development in Mice with Alport Syndrome, Study Shows

A protein receptor that is activated in the early phase of chronic kidney disease contributes to the development of bone, cardiac and kidney dysfunction, according to a study using a mouse model of Alport syndrome.

The title of the research was “The activin receptor is stimulated in the skeleton, vasculature, heart, and kidney during chronic kidney disease.” It was published in the journal Kidney International, the official journal of the International Society of Nephrology.

Chronic kidney disease-mineral and bone disorder, or CKD-MBD, is a major contributor to death from  kidney disease. The disorder, whose hallmarks include skeletal, vascular, and cardiac dysfunction, manifests itself early in chronic kidney disease patients.

A recent study suggested that a protein receptor known as activin receptor type IIA, ActRIIA, plays a key role in kidney disease progression and the development of CKD-MBD.

The receptor regulates the functions of proteins known as activins. They are members of the transforming growth factor-beta (TGF-beta) superfamily of proteins, which play roles in cell differentiation, proliferation, and inflammation.

Researchers used a mouse model of Alport syndrome to look at the role the ActRIIA receptor plays in the development of CKD-MBD.

They discovered that chronic kidney disease activated ActRIIA signaling in the mice, then confirmed the finding in two other CKD animal models.

Researchers also found signs of severe CKD and CKD-MBD in the mice’s skeletons, blood vessels, hearts, and kidneys.

An ActRIIA inhibitor called RAP-011 reduced many of the kidney disease features in the mice. For example, it blocked CKD stimulation of cardiac hypertrophy — abnormal enlargement or thickening of heart muscle.

It also reversed CKD-triggered dysfunction of osteoblasts and a process that osteoblasts govern known as bone tissue resorption. Osteoclasts break down the tissue in bones and release the minerals, which leads to calcium being transferred from bone tissue to the blood. The process is called bone resorption.

By reversing bone resorption dysfunction, RAP-011 led to increased bone formation.

In addition, it preserved the mice’s kidney function, compared with untreated mice.

Overall, these results suggested that “the activation of ActRIIA signaling during early CKD contributes to the CKD-MBD components of osteodystrophy [defective bone development] and cardiovascular disease and to renal fibrosis [kidney tissue scarring],” the researchers wrote.

“Thus, the inhibition of ActRIIA signaling is efficacious in improving and delaying CKD-MBD in this model of Alport syndrome,” they concluded.

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