Circulating bone morphogenetic protein 1-3 isoform increases renal fibrosis

Area of Science:

• Biochemistry
• Nephrology
• Molecular Biology

Background:

• Bone morphogenetic proteins (BMPs) are known for their roles in organ regeneration via local signaling.
• The presence and function of BMPs in systemic circulation, particularly in kidney disease, remain largely unexplored.

Purpose of the Study:

• To investigate the existence and functional role of circulating BMPs in chronic kidney disease (CKD).
• To determine if circulating BMP1-3 contributes to renal fibrosis and identify potential therapeutic targets for CKD.

Main Methods:

• Liquid chromatography-mass spectrometry was used to identify BMPs in plasma from healthy volunteers and CKD patients.
• Endogenous BMP1-3 was isolated and its enzymatic activity assessed in vitro.
• The effects of recombinant BMP1-3 and a BMP1-3-neutralizing antibody were evaluated in CKD rat models.
• Gene transcription analysis was performed in HEK293 cells and remnant kidneys.

Main Results:

• BMP6, GDF15, and the BMP1-3 isoform were identified in human plasma.
• Circulating BMP1-3 functions as an active enzyme, promoting renal fibrosis and reducing survival in CKD rats.
• Neutralization of BMP1-3 ameliorated renal fibrosis, preserved kidney function, and increased survival in CKD rats.
• BMP1-3 signaling involves integrin β1 and upregulates profibrotic genes like collagen type I and TGFβ1, while decreasing decorin expression.

Conclusions:

• Circulating BMP1-3 is a novel profibrotic factor in chronic kidney disease.
• Inhibition of circulating BMP1-3 represents a promising therapeutic strategy for reducing renal fibrosis in CKD.
• Targeting the BMP1-3 pathway offers a potential new avenue for CKD treatment.