The activin receptor is stimulated in the skeleton, vasculature, heart, and kidney during chronic kidney disease

Kidney Int. 2018 Jan;93(1):147-158. doi: 10.1016/j.kint.2017.06.016. Epub 2017 Aug 23.

Abstract

We examined activin receptor type IIA (ActRIIA) activation in chronic kidney disease (CKD) by signal analysis and inhibition in mice with Alport syndrome using the ActRIIA ligand trap RAP-011 initiated in 75-day-old Alport mice. At 200 days of age, there was severe CKD and associated Mineral and Bone Disorder (CKD-MBD), consisting of osteodystrophy, vascular calcification, cardiac hypertrophy, hyperphosphatemia, hyperparathyroidism, elevated FGF23, and reduced klotho. The CKD-induced bone resorption and osteoblast dysfunction was reversed, and bone formation was increased by RAP-011. ActRIIA inhibition prevented the formation of calcium apatite deposits in the aortic adventitia and tunica media and significantly decreased the mean aortic calcium concentration from 0.59 in untreated to 0.36 mg/g in treated Alport mice. Aortic ActRIIA stimulation in untreated mice increased p-Smad2 levels and the transcription of sm22α and αSMA. ActRIIA inhibition reversed aortic expression of the osteoblast transition markers Runx2 and osterix. Heart weight was significantly increased by 26% in untreated mice but remained normal during RAP-011 treatment. In 150-day-old mice, GFR was significantly reduced by 55%, but only by 30% in the RAP-011-treated group. In 200-day-old mice, the mean BUN was 100 mg/dl in untreated mice compared to 60 mg/dl in the treated group. In the kidneys of 200-day-old mice, ActRIIA and p-Smad2 were induced and MCP-1, fibronectin, and interstitial fibrosis were stimulated; all were attenuated by RAP-011 treatment. Hence, the activation of ActRIIA signaling during early CKD contributes to the CKD-MBD components of osteodystrophy and cardiovascular disease and to renal fibrosis. Thus, the inhibition of ActRIIA signaling is efficacious in improving and delaying CKD-MBD in this model of Alport syndrome.

Keywords: bone; cardiovascular disease; chronic kidney disease; fibrosis; mineral metabolism; vascular calcification.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Actins / metabolism
  • Activin Receptors, Type II / antagonists & inhibitors
  • Activin Receptors, Type II / genetics
  • Activin Receptors, Type II / metabolism*
  • Animals
  • Blood Vessels / metabolism
  • Blood Vessels / pathology
  • Blood Vessels / physiopathology
  • Bone Remodeling
  • Bone Resorption / genetics
  • Bone Resorption / metabolism*
  • Bone Resorption / physiopathology
  • Bone Resorption / prevention & control
  • Bone and Bones / metabolism
  • Bone and Bones / pathology
  • Bone and Bones / physiopathology
  • Cardiomegaly / genetics
  • Cardiomegaly / metabolism*
  • Cardiomegaly / physiopathology
  • Cardiomegaly / prevention & control
  • Chronic Kidney Disease-Mineral and Bone Disorder / genetics
  • Chronic Kidney Disease-Mineral and Bone Disorder / metabolism*
  • Chronic Kidney Disease-Mineral and Bone Disorder / physiopathology
  • Chronic Kidney Disease-Mineral and Bone Disorder / prevention & control
  • Collagen Type IV / deficiency
  • Collagen Type IV / genetics
  • Core Binding Factor Alpha 1 Subunit / metabolism
  • Disease Models, Animal
  • Fibroblast Growth Factor-23
  • Fibrosis
  • Glomerular Filtration Rate
  • Kidney / metabolism
  • Kidney / pathology
  • Kidney / physiopathology
  • Mice, Knockout
  • Microfilament Proteins / metabolism
  • Muscle Proteins / metabolism
  • Myocardium / metabolism
  • Myocardium / pathology
  • Nephritis, Hereditary / drug therapy
  • Nephritis, Hereditary / genetics
  • Nephritis, Hereditary / metabolism*
  • Nephritis, Hereditary / physiopathology
  • Phosphorylation
  • Recombinant Fusion Proteins / pharmacology
  • Renal Insufficiency, Chronic / genetics
  • Renal Insufficiency, Chronic / metabolism*
  • Renal Insufficiency, Chronic / physiopathology
  • Renal Insufficiency, Chronic / prevention & control
  • Signal Transduction
  • Smad2 Protein / metabolism
  • Sp7 Transcription Factor / metabolism
  • Vascular Calcification / genetics
  • Vascular Calcification / metabolism*
  • Vascular Calcification / physiopathology
  • Vascular Calcification / prevention & control
  • Vascular Remodeling
  • Ventricular Remodeling

Substances

  • ActRIIA-mIgG2aFc fusion protein
  • Actins
  • Col4a5 protein, mouse
  • Collagen Type IV
  • Core Binding Factor Alpha 1 Subunit
  • Fgf23 protein, mouse
  • Microfilament Proteins
  • Muscle Proteins
  • Recombinant Fusion Proteins
  • Runx2 protein, mouse
  • Smad2 Protein
  • Smad2 protein, mouse
  • Sp7 Transcription Factor
  • Sp7 protein, mouse
  • Tagln protein, mouse
  • alpha-smooth muscle actin, mouse
  • Fibroblast Growth Factor-23
  • Activin Receptors, Type II
  • activin receptor type II-A