The caveolin-1 regulated protein follistatin protects against diabetic kidney disease.

Abstract

Glomerular matrix protein accumulation, mediated largely by mesangial cells, is central to the pathogenesis of diabetic kidney disease. Our previous studies showed that the membrane microdomains caveolae and their marker protein caveolin-1 regulate matrix protein synthesis in mesangial cells in response to diabetogenic stimuli, and that caveolin-1 knockout mice are protected against diabetic kidney disease. In a screen to identify the molecular mechanism underlying this protection, we also established that secreted antifibrotic glycoprotein follistatin is significantly upregulated by caveolin-1 deletion. Follistatin potently neutralizes activins, members of the transforming growth factor-β superfamily. A role for activins in diabetic kidney disease has not yet been established. Therefore, in vitro, we confirmed the regulation of follistatin by caveolin-1 in primary mesangial cells and showed that follistatin controls both basal and glucose-induced matrix production through activin inhibition. In vivo, we found activin A upregulation by immunohistochemistry in both mouse and human diabetic kidney disease. Importantly, administration of follistatin to type 1 diabetic Akita mice attenuated early diabetic kidney disease, characterized by albuminuria, hyperfiltration, basement membrane thickening, loss of endothelial glycocalyx and podocyte nephrin, and glomerular matrix accumulation. Thus, activin A is an important mediator of high glucose-induced profibrotic responses in mesangial cells, and follistatin may be a potential novel therapy for the prevention of diabetic kidney disease.

• Authors: Dan Zhang, Agata L Gava, Richard Van Krieken, Neel Mehta, Renzhong Li, Bo Gao, Eric M Desjardins, Gregory R Steinberg, Thomas Hawke, Joan C Krepinsky
• Journal: Kidney international (Kidney Int) Vol. 96 Issue 5 Pg. 1134-1149 (11 2019) ISSN: 1523-1755 [Electronic] United States
• PMID: 31492508 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Caveolin 1
• Extracellular Matrix Proteins
• Follistatin
• activin A
• Activins

Topics

• Activins (metabolism)
• Animals
• Caveolin 1 (metabolism)
• Diabetic Nephropathies (metabolism, prevention & control)
• Drug Evaluation, Preclinical
• Extracellular Matrix Proteins (biosynthesis)
• Follistatin (metabolism, therapeutic use)
• Male
• Mesangial Cells (metabolism)
• Mice, Knockout