ArticleKidney international2012
Divergent roles of Smad3 and PI3-kinase in murine adriamycin nephropathy indicate distinct mechanisms of proteinuria and fibrogenesis.
Article in Kidney international, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 24 citations in OpenAlex.
- Heparanase Increases Podocyte Survival and Autophagic Flux after Adriamycin-Induced Injury.International journal of molecular sciences · 2022Article
- The motor protein Myo1c regulates transforming growth factor-β-signaling and fibrosis in podocytes.Kidney international · 2019Article
- Hypoxia-inducible factor-1α promotes glomerulosclerosis and regulates COL1A2 expression through interactions with Smad3.Kidney international · 2016Article
- Anti-TGF-β Antibody, 1D11, Ameliorates Glomerular Fibrosis in Mouse Models after the Onset of Proteinuria.PloS one · 2016Article
- Smad3 deficiency protects mice from obesity-induced podocyte injury that precedes insulin resistance.Kidney international · 2015Article
- GQ5 Hinders Renal Fibrosis in Obstructive Nephropathy by Selectively Inhibiting TGF-β-Induced Smad3 Phosphorylation.Journal of the American Society of Nephrology : JASN · 2015Article
- Pentoxifylline Attenuates Proteinuria in Anti-Thy1 Glomerulonephritis via Downregulation of Nuclear Factor-κB and Smad2/3 Signaling.Molecular medicine (Cambridge, Mass.) · 2015Article
- TGFβ-induced deptor suppression recruits mTORC1 and not mTORC2 to enhance collagen I (α2) gene expression.PloS one · 2014Article
- Hypoxia-inducible factor-2α and TGF-β signaling interact to promote normoxic glomerular fibrogenesis.American journal of physiology. Renal physiology · 2013Article
- TGF-β/Smad3 activates mammalian target of rapamycin complex-1 to promote collagen production by increasing HIF-1α expression.American journal of physiology. Renal physiology · 2013Article
- Transforming growth factor-beta and the glomerular filtration barrier.Kidney research and clinical practice · 2013Article
- The heme oxygenase system rescues hepatic deterioration in the condition of obesity co-morbid with type-2 diabetes.PloS one · 2013Article
- PI3-kinase and TGF-β in glomerular nephropathy: which comes first?Kidney international · 2012Article
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6 authors at 2 institutions in 1 country.
Funding
Abstract
Multiple transforming growth factor (TGF)-β-induced fibrogenic signals have been described in vitro. To evaluate mechanisms in vivo, we used an adriamycin nephropathy model in 129x1/Svj mice that display massive proteinuria by days 5 to 7 and pathological findings similar to human focal segmental glomerulosclerosis by day 14. TGF-β mRNA expression increased after day 7 along with nuclear translocation of the TGF-β receptor-specific transcription factor Smad3. Inhibiting TGF-β prevented both pathological changes and type-I collagen and fibronectin mRNA expression, but proteinuria persisted. Renal Akt was phosphorylated in adriamycin-treated mice, suggesting PI3-kinase activation. Expression of mRNA for the p110γ isozyme of PI3-kinase was specifically increased and p110γ colocalized with nephrin by immunohistochemistry early in disease. Nephrin levels subsequently decreased. Inhibition of p110γ by AS605240 preserved nephrin expression and prevented proteinuria. In cultured podocytes, adriamycin stimulated p110γ expression. AS605240, but not a TGF-β receptor kinase inhibitor, prevented adriamycin-induced cytoskeletal disorganization and apoptosis, supporting a role for p110γ in podocyte injury. AS605240, at a dose that decreased proteinuria, prevented renal collagen mRNA expression in vivo but did not affect TGF-β-stimulated collagen induction in vitro. Thus, PI3-kinase p110γ mediates initial podocyte injury and proteinuria, both of which precede TGF-β-mediated glomerular scarring.
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