Tenascin-C Is a Major Component of the Fibrogenic Niche in Kidney Fibrosis

• Published in: Journal of the American Society of Nephrology Vol. 28; no. 3; pp. 785 - 801
• Main Authors: Fu, Haiyan, Tian, Yuan, Zhou, Lili, Zhou, Dong, Tan, Roderick J., Stolz, Donna B., Liu, Youhua
• Format: Journal Article
• Language: English
• Published: United States American Society of Nephrology 01.03.2017
• Subjects: Animals; Basic Research; Cell Proliferation; Fibroblasts - pathology; Fibrosis - etiology; Kidney - chemistry; Kidney - pathology; Kidney Diseases - etiology; Kidney Diseases - pathology; Male; Mice; Mice, Inbred C57BL; Tenascin - analysis; Tenascin - physiology; renal fibrosis; extracellular matrix; fibroblast
• ISSN: 1046-6673; 1533-3450; 1533-3450
• DOI: 10.1681/ASN.2016020165

Kidney fibrosis initiates at certain focal sites in which the fibrogenic niche provides a specialized microenvironment that facilitates fibroblast activation and proliferation. However, the molecular identity of these fibrogenic niches is poorly characterized. Here, we determined whether tenascin-C (TNC), an extracellular matrix glycoprotein, is a component of the fibrogenic niche in kidney fibrosis. In vivo , TNC expression increased rapidly in kidneys subjected to unilateral ureteral obstruction or ischemia/reperfusion injury and predominantly localized at the foci rich in fibroblasts in renal interstitium. In vitro , TNC selectively promoted renal interstitial fibroblast proliferation, bromodeoxyuridine incorporation, and the expression of proliferation-related genes. The mitogenic activity of TNC required the integrin/focal adhesion kinase/mitogen-activated protein kinase signaling cascade. Using decellularized extracellular matrix scaffolds, we found that TNC-enriched scaffolds facilitated fibroblast proliferation, whereas TNC-deprived scaffolds inhibited proliferation. Matrix scaffold prepared from fibrotic kidney also promoted greater ex vivo fibroblast proliferation than did scaffolds prepared from healthy kidney. Conversely, small interfering RNA-mediated knockdown of TNC in vivo repressed injury-induced fibroblast expansion and renal fibrosis. These studies identify TNC as a major constituent of the fibrogenic niche that promotes fibroblast proliferation, and illustrate a pivotal role for the TNC-enriched microenvironment in kidney fibrogenesis.