Epithelial Cell TGFβ Signaling Induces Acute Tubular Injury and Interstitial Inflammation

Gentle, Madeleine E.; Shi, Shaolin; Daehn, Ilse; Zhang, Taoran; Qi, Haiying; Yu, Liping; D’Agati, Vivette D.; Schlöndorff, Detlef; Böttinger, Erwin P.

doi:10.1681/asn.2012101024

Cited by 68 publications

(53 citation statements)

References 61 publications

(83 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Some early studies reported the transient activation of TGF-β signaling in AKI that may promote kidney tubular cell proliferation and apoptosis 39, 40 . In sharp contrast, most recent studies suggested that TGF-β is an injurious factor and inhibition of TGF-β pathway may reduce renal tubular injury 41–44 . Using a mouse model of inducible TGF-β expression in kidney tubular cells, Koesters R et al demonstrated that tubular TGF-β activation may initially stimulate interstitial cell proliferation, but sustained TGF-β induction leads to tubular degeneration through autophagy-mediated tubular decomposition 45 .…”

Section: Potential Mechanisms Underlying the Susceptibility And mentioning

confidence: 89%

AKI on CKD: heightened injury, suppressed repair, and the underlying mechanisms

Wei

Liu

et al. 2017

Kidney International

312

222

View full text Add to dashboard Cite

Acute kidney injury (AKI) and chronic kidney disease (CKD) are inter-connected. While AKI-to-CKD transition has been intensively studied, the information of AKI on CKD is very limited. Nonetheless, AKI, when occurring in CKD patients, is known to be more severe and difficult to recover. CKD is associated with significant changes in cell signaling in kidney tissues, including the activation of TGF-β, p53, HIF, and major developmental pathways. At the cellular level, CKD is characterized by mitochondrial dysfunction, oxidative stress, and aberrant autophagy. At the tissue level, CKD is characterized by chronic inflammation and vascular dysfunction. These pathological changes may contribute to the heightened sensitivity of, and non-recovery from, AKI in CKD patients.

show abstract

Section: Potential Mechanisms Underlying the Susceptibility And mentioning

confidence: 89%

AKI on CKD: heightened injury, suppressed repair, and the underlying mechanisms

Wei

Liu

et al. 2017

Kidney International

312

222

View full text Add to dashboard Cite

show abstract

“…7A). It has been recently shown that TGF-␤ 1 directly injures tubular epithelial cells (28), and the protection after Fg depletion could partially be attributed to this mechanism. Although histological and functional analyses did not reveal differences between groups on day 1, it is possible that this becomes apparent subsequently, as AKI peaks on day 2 and persists through day 3 after FA injection.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological and genetic depletion of fibrinogen protects from kidney fibrosis

Craciun

Ajay

Hoffmann

et al. 2014

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

Fibrinogen (Fg) has been implicated in the pathogenesis of several fibrotic disorders by acting as a profibrotic ligand for a variety of cellular surface receptors and by modulating the provisional fibrin matrix formed after injury. We demonstrated increased renal Fg expression after unilateral ureteral obstruction and folic acid (FA) nephropathy in mice, respectively. Urinary Fg excretion was also increased in FA nephropathy. Using in vitro and in vivo approaches, our results suggested that IL-6 mediates STAT3 activation in kidney fibrosis and that phosphorylated (p)STAT3 binds to Fgα, Fgβ, and Fgγ promoters in the kidney to regulate their transcription. Genetically modified Fg heterozygous mice (∼75% of normal plasma Fg levels) exhibited only 3% kidney interstitial fibrosis and tubular atrophy after FA nephropathy compared with 24% for wild-type mice. Fibrinogenolysis through Ancrod administration after FA reduced interstitial fibrosis more than threefold compared with vehicle-treated control mice. Mechanistically, we show that Fg acts synergistically with transforming growth factor (TGF)-β1 to induce fibroblast proliferation and activates TGF-β1/pSMAD2 signaling. This study offers increased understanding of Fg expression and molecular interactions with TGF-β1 in the progression to kidney fibrosis and, importantly, indicates that fibrinogenolytics like Ancrod present a treatment opportunity for a yet intractable disease.

show abstract

“…Examples of receptors involved in AKI-mediated injury include the FAS receptor and TGFb receptor. 40,41 Examples of receptors involved in epithelial cytoprotection and repair include the EGF receptor, 42 HGF receptor (c-Met), 43 sphingosine-1-phosphate receptor, 44 and netrin-1 receptor. 45 Many questions relating to the role of receptors in AKI remain unanswered, including the sources of the putative ligands, mechanisms of receptor activation, and signaling pathways involved in protection from injury or involved with epithelial repair.…”

Section: Receptorsmentioning

confidence: 99%

Cellular and Molecular Mechanisms of AKI

Agarwal

Dong

Harris

et al. 2016

JASN

174

151

View full text Add to dashboard Cite

In this article, we review the current evidence for the cellular and molecular mechanisms of AKI, focusing on epithelial cell pathobiology and related cell-cell interactions, using ischemic AKI as a model. Highlighted are the clinical relevance of cellular and molecular targets that have been investigated in experimental models of ischemic AKI and how such models might be improved to optimize translation into successful clinical trials. In particular, development of more context-specific animal models with greater relevance to human AKI is urgently needed. Comorbidities that could alter patient susceptibility to AKI, such as underlying diabetes, aging, obesity, cancer, and CKD, should also be considered in developing these models. Finally, harmonization between academia and industry for more clinically relevant preclinical testing of potential therapeutic targets and better translational clinical trial design is also needed to achieve the goal of developing effective interventions for AKI. Cellular and molecular mechanisms of AKI have been extensively investigated in a variety of experimental models, through which a number of candidate therapies for AKI have been identified. This article reviews the current evidence by dissecting the cellular and molecular mechanisms of AKI, focusing on epithelial cell pathobiology and related cell-cell interactions, and using the example of ischemic AKI to describe our approach. Specifically, we reviewed the cellular and molecular epithelial cell targets that have been investigated in experimental models of ischemic AKI, and considered the clinical relevance of these models in human AKI and how such models might be improved to optimize translation into successful clinical trials. We have structured our review to answer two key questions:

show abstract

Epithelial Cell TGFβ Signaling Induces Acute Tubular Injury and Interstitial Inflammation

Cited by 68 publications

References 61 publications

AKI on CKD: heightened injury, suppressed repair, and the underlying mechanisms

AKI on CKD: heightened injury, suppressed repair, and the underlying mechanisms

Pharmacological and genetic depletion of fibrinogen protects from kidney fibrosis

Cellular and Molecular Mechanisms of AKI

Contact Info

Product

Resources

About