ArticleAmerican journal of physiology. Renal physiology2013
Notch4-dependent antagonism of canonical TGF-β1 signaling defines unique temporal fluctuations of SMAD3 activity in sheared proximal tubular epithelial cells.
Article in American journal of physiology. Renal physiology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 16 citations in OpenAlex.
- Advances in mechanical force-induced adaptive responses and pathological transition of renal tubular epithelial cells.Frontiers in cell and developmental biology · 2026Review
- Review
- The Complex Interplay of TGF-β and Notch Signaling in the Pathogenesis of Fibrosis.International journal of molecular sciences · 2024Review
- Advancements in therapeutic development: kidney organoids and organs on a chip.Kidney international · 2024Review
- Shaking culture enhances chondrogenic differentiation of mouse induced pluripotent stem cell constructs.Scientific reports · 2020Article
- Comprehensive transcriptome analysis of fluid shear stress altered gene expression in renal epithelial cells.Journal of cellular physiology · 2018Article
- Fluid shear stress-induced TGF-β/ALK5 signaling in renal epithelial cells is modulated by MEK1/2.Cellular and molecular life sciences : CMLS · 2017Article
- Notch in fibrosis and as a target of anti-fibrotic therapy.Pharmacological research · 2016Review
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2 authors at 1 institution in 1 country.
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Abstract
Transforming growth factor-β1 (TGF-β1) is thought to drive fibrogenesis in numerous organ systems. However, we recently established that ectopic expression of TGF-β1 abrogates collagen accumulation via canonical SMAD signaling mechanisms in a shear-induced model of kidney fibrosis. We herein delineate the temporal control of endogenous TGF-β1 signaling that generates sustained synchronous fluctuations in TGF-β1 cascade activation in shear-stimulated proximal tubule epithelial cells (PTECs). During 8-h exposure to physiological shear stress (0.3 dyn/cm²), PTECs experience in situ oscillatory concentrations of active endogenous TGF-β1 that are ~10-fold greater than those detected under higher stress regimes (2-4 dyn/cm²). The elevated levels of intrinsic TGF-β1 maturation observed under physiological conditions are accompanied by persistent downstream SMAD3 activation. Pathological shear stresses (2 dyn/cm²) first elicit temporal variations in phosphorylated SMAD3 with an apparent period of ~6 h, whereas even higher stresses (4 dyn/cm²) abolish SMAD3 activation. These divergent patterns of SMAD3 activation are attributed to varying levels of Notch4-dependent phospho-SMAD3 degradation. Depletion of Notch4 in shear-stimulated PTECs eventually increases the levels of active TGF-β1 protein by approximately fivefold, recovers stable SMAD phosphorylation and ubiquitinated SMAD species, and attenuates collagen accumulation. Collectively, these data establish Notch4 as a critical mediator of shear-induced fibrosis and further reinforce the renoprotective effects of canonical TGF-β1 signaling.
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