Deleting the TGF-β Receptor Attenuates Acute Proximal Tubule Injury

Gewin, Leslie; Vadivelu, Sangeetha; Neelisetty, Surekha; Srichai, Manakan B.; Paueksakon, Paisit; Pozzi, Ambra; Harris, Raymond C.; Zent, Roy

doi:10.1681/asn.2012020139

Cited by 72 publications

(81 citation statements)

References 49 publications

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“…2,3,24 Its signaling is usually profibrotic, but is not without exceptions. For instance, although conditional deletion of TbRII in proximal tubular epithelial cells inhibits tubulointerstitial fibrosis in kidneys with UUO, 19 the opposite effect is observed when deletion targets epithelia of the collecting duct. 18 ECs represent a unique target for TGF-b because they are the predominant cell type expressing an alternative receptor, ALK1.…”

Section: Discussionmentioning

confidence: 99%

“…17 The same strategy has been reported for epithelial cells in the proximal tubule and collecting duct. 18,19 However, there are no published data on its ablation in the endothelium partly because of the unavailability of endothelial TbRII knockout mice due to the embryonic lethality. 9,10 To address the question of whether endothelial TGF-b signals contribute to renal fibrosis, we utilized mice with partial ablation of TbRII in this study (i.e., mice heterozygous for TbRII), and investigated the role of endothelial TGF-b signaling in renal fibrosis of the folic acid nephropathy (FAN) and unilateral ureteral obstruction (UUO) models.…”

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confidence: 99%

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Curtailing Endothelial TGF-β Signaling Is Sufficient to Reduce Endothelial-Mesenchymal Transition and Fibrosis in CKD

Xavier

Vasko

Matsumoto

et al. 2015

Journal of the American Society of Nephrology

135

109

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Excessive TGF-b signaling in epithelial cells, pericytes, or fibroblasts has been implicated in CKD. This list has recently been joined by endothelial cells (ECs) undergoing mesenchymal transition. Although several studies focused on the effects of ablating epithelial or fibroblast TGF-b signaling on development of fibrosis, there is a lack of information on ablating TGF-b signaling in the endothelium because this ablation causes embryonic lethality. We generated endothelium-specific heterozygous TGF-b receptor knockout (TbRII endo+/2 ) mice to explore whether curtailed TGF-b signaling significantly modifies nephrosclerosis.These mice developed normally, but showed enhanced angiogenic potential compared with TbRII endo+/+ mice under basal conditions. After induction of folic acid nephropathy or unilateral ureteral obstruction, TbRII endo+/2 mice exhibited less tubulointerstitial fibrosis, enhanced preservation of renal microvasculature, improvement in renal blood flow, and less tissue hypoxia than TbRII endo+/+ counterparts. In addition, partial deletion of TbRII in the endothelium reduced endothelial-to-mesenchymal transition (EndoMT). TGF-b-induced canonical Smad2 signaling was reduced in TbRII +/2 ECs; however, activin receptor-like kinase 1 (ALK1)-mediated Smad1/5 phosphorylation in TbRII +/2 ECs remained unaffected. Furthermore, the S-endoglin/L-endoglin mRNA expression ratio was significantly lower in TbRII +/2 ECs compared with TbRII +/+ ECs. These observations support the hypothesis that EndoMT contributes to renal fibrosis and curtailing endothelial TGF-b signals favors Smad1/5 proangiogenic programs and dictates increased angiogenic responses. Our data implicate endothelial TGF-b signaling and EndoMT in regulating angiogenic and fibrotic responses to injury.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Curtailing Endothelial TGF-β Signaling Is Sufficient to Reduce Endothelial-Mesenchymal Transition and Fibrosis in CKD

Xavier

Vasko

Matsumoto

et al. 2015

Journal of the American Society of Nephrology

135

109

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“…Our findings are also consistent with data recently obtained by Gewin et al in a complementary system where TbR2 is deleted in proximal tubular cells, which resulted in decreased tubular damage and apoptosis after mercuric chloride-induced AKI. 49 Thus, TGFb signaling alone is sufficient to cause tubular epithelial cell dedifferentiation, apoptosis, and necrosis. This is consistent with in vitro experiments showing that TGFb can induce apoptosis via transcriptional regulation of apoptotic factors.…”

Section: Discussionmentioning

confidence: 99%

Epithelial Cell TGFβ Signaling Induces Acute Tubular Injury and Interstitial Inflammation

Gentle

Shi

Daehn

et al. 2013

Journal of the American Society of Nephrology

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TGFb signaling plays a central role in the development of acute and chronic kidney diseases. Previous in vivo studies involved systemic alteration of TGFb signaling, however, limiting conclusions about the direct role of TGFb in tubular cell injury. Here, we generated a double transgenic mouse that inducibly expresses a ligand-independent constitutively active TGFb receptor type 1 (TbR1) kinase specifically in tubular epithelial cells, with expression restricted by the Pax8 promoter. In this model, activation of TGFb signaling in the tubular epithelium alone was sufficient to cause AKI characterized by marked tubular cell apoptosis and necrosis, oxidative stress, dedifferentiation and regenerative cell proliferation, reduced renal function, and interstitial accumulation of inflammatory cells. This tubular injury was associated with mitochondrial-derived generation of reactive oxygen species (ROS), but cell damage and apoptosis were partially independent of mitochondrial-derived ROS.

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“…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

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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:

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Deleting the TGF-β Receptor Attenuates Acute Proximal Tubule Injury

Cited by 72 publications

References 49 publications

Curtailing Endothelial TGF-β Signaling Is Sufficient to Reduce Endothelial-Mesenchymal Transition and Fibrosis in CKD

Curtailing Endothelial TGF-β Signaling Is Sufficient to Reduce Endothelial-Mesenchymal Transition and Fibrosis in CKD

Epithelial Cell TGFβ Signaling Induces Acute Tubular Injury and Interstitial Inflammation

Cellular and Molecular Mechanisms of AKI

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