Magnification of Electron Micrographs

Eyden, Brian P

doi:10.1093/ajcp/109.2.237

Cited by 1 publication

(2 citation statements)

References 3 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…They are more profibrotic than resting fibroblasts and are thought to be the primary source of the scar-forming extracellular matrix proteins in many solid organs, including kidneys (41,44). The molecular basis of renal myofibroblast accumulation remains incompletely understood.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

A Novel Signaling Pathway

Zhang

Kernan

Thomas

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

The nicotinic acetylcholine receptor ␣1 (nAChR␣1) was investigated as a potential fibrogenic molecule in the kidney, given reports that it may be an alternative urokinase (urokinase plasminogen activator; uPA) receptor in addition to the classical receptor uPAR. In a mouse obstructive uropathy model of chronic kidney disease, interstitial fibroblasts were identified as the primary cell type that bears nAChR␣1 during fibrogenesis. Silencing of the nAChR␣1 gene led to significantly fewer interstitial ␣SMA ؉ myofibroblasts (2.8 times decreased), reduced interstitial cell proliferation (2.6 times decreased), better tubular cell preservation (E-cadherin 14 times increased), and reduced fibrosis severity (24% decrease in total collagen). The myofibroblast-inhibiting effect of nAChR␣1 silencing in uPAsufficient mice disappeared in uPA-null mice, suggesting that a uPA-dependent fibroblastic nAChR␣1 pathway promotes renal fibrosis. To further establish this possible ligand-receptor relationship and to identify downstream signaling pathways, in vitro studies were performed using primary cultures of renal fibroblasts. 35 S-Labeled uPA bound to nAChR␣1 with a K d of 1.6 ؋ 10 ؊8 M, which was displaced by the specific nAChR␣1 inhibitor D-tubocurarine in a dose-dependent manner. Pre-exposure of uPA to the fibroblasts inhibited [ 3 H]nicotine binding. The uPA binding induced a cellular calcium influx and an inward membrane current that was entirely prevented by D-tubocurarine preincubation or nAChR␣1 silencing. By mass spectrometry phosphoproteome analyses, uPA stimulation phosphorylated nAChR␣1 and a complex of signaling proteins, including calcium-binding proteins, cytoskeletal proteins, and a nucleoprotein. This signaling pathway appears to regulate the expression of a group of genes that transform renal fibroblasts into more active myofibroblasts characterized by enhanced proliferation and contractility. This new fibrosis-promoting pathway may also be relevant to disorders that extend beyond chronic kidney disease.

show abstract

Section: Discussionmentioning

confidence: 99%

“…5a). Northern blot analyses were performed to investigate the effects of uPA-nAChR␣1/ uPAR interactions on fibroblast ␣SMA expression, a cytoskeleton protein marker for "activated" fibroblasts or myofibroblast phenotypic transformation (41,42) (Fig. 5b).…”

Section: Renal Expression Of Nachr␣1 and Acetylcholine Duringmentioning

confidence: 99%