STAT6 deficiency inhibits tubulointerstitial fibrosis in obstructive nephropathy

Yukawa, Kazunori; Kishino, Masanori; Goda, Mikako; Xiang, Lei; Kimura, Akihiko; Tanaka, Tetsuji; Bai, Tao; Owada-Makabe, Kyoko; Tsubota, Yuji; Umemura, Takashi; Ichinose, Masakazu; Maeda, Masanobu; Takeda, Kiyoshi; Akira, Shizuo

doi:10.3892/ijmm.15.2.225

Cited by 12 publications

(10 citation statements)

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“…STAT6 Ϫ/Ϫ mice were more susceptible to myasthenia gravis (45). In other Th1 models of autoimmunity STAT6 was also shown to exert a protective effect (46). According to our present findings these effects might result from the STAT6 effects increasing Treg cell generation.…”

Section: Discussionmentioning

confidence: 47%

Agonist-Driven Development of CD4+CD25+Foxp3+ Regulatory T Cells Requires a Second Signal Mediated by Stat6

Sanchez-Guajardo

Tanchot

O’Malley

et al. 2007

The Journal of Immunology

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The factors that induce Foxp3 expression and regulatory T (Treg) cell development remain unknown. In this study, we investigated the role of STAT4 and STAT6 in agonist-driven generation of Ag-specific Foxp3-expressing Treg cells. Our findings indicate that fully efficient induction of Foxp3 expression and development of Ag-specific Treg cells requires the synergistic action of two signals: a TCR-mediated signal and a second signal mediated by STAT6. Indeed, by comparing the development of wild-type and STAT4- and STAT6-deficient hemagglutinin-specific T cells in the presence of hemagglutinin Ag, we found that the absence of STAT6 impaired the generation of Ag-specific CD4+CD25+Foxp3+ cells. Moreover, in transgenic mice expressing a constitutively active form of STAT6, we found that the fraction of CD4+Foxp3+ cells exceeds that of control wild-type littermates. Overall these findings support a role for the STAT6 pathway in Treg cell development and maintenance.

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Section: Discussionmentioning

confidence: 47%

Agonist-Driven Development of CD4+CD25+Foxp3+ Regulatory T Cells Requires a Second Signal Mediated by Stat6

Sanchez-Guajardo

Tanchot

O’Malley

et al. 2007

The Journal of Immunology

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“…Pharmacological inhibition of NF-κB signalling by pyrrolidine dithiocarbamate significantly diminished kidney injury and ameliorated tubular degeneration, tubular necrosis and tubulointerstitial inflammation in models of kidney fibrosis induced by folate or adenine overload in mice 33,34 . Similarly, genetic deletion of STAT has been shown to ameliorate kidney fibrosis in mouse models 29,30,35 . These studies support the key role of NF-κB, STAT and inflammation in the development of fibrosis.…”

Section: Mechanisms Of Renal Fibrosismentioning

confidence: 99%

Developmental signalling pathways in renal fibrosis: the roles of Notch, Wnt and Hedgehog

et al. 2016

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Kidney fibrosis is the histological manifestation of functional decline in the kidney. Fibrosis is a reactive process that develops in response to excessive epithelial injury and inflammation. Here, we describe how three key developmental signalling pathways—Notch, Wnt and Hedgehog—are reactivated in response to kidney injury. Although transient activation of these pathways is needed for repair of injured tissue, their sustained activation promotes fibrosis. Excessive Wnt and Notch expression prohibit epithelial differentiation whereas increased Wnt and Hh expression induce fibroblast proliferation and myofibroblastic transdifferentiation. Notch, Wnt and Hedgehog are fundamentally different signalling mechanisms, but their choreographed activation seems to be just as important for fibrosis as it is for embryonic kidney development. Decreasing the activity of Notch, Wnt, or Hh signalling could potentially be a new therapeutic strategy to ameliorate the development of chronic kidney disease.

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“…Yukawa et al used mice with deletion of the first coding exon of STAT6 and showed that these mice had more apoptotic cells and F4/80 + cells, exhibited less severe renal fibrosis, and accumulated less collagen I in the obstructed kidneys. 35 Macrophages play an important role in the regulation of fibrosis. 36 Recent evidence indicates that macrophages are heterogeneous and display a remarkable plasticity.…”

Section: Discussionmentioning

confidence: 99%

JAK3/STAT6 Stimulates Bone Marrow–Derived Fibroblast Activation in Renal Fibrosis

Yan

Zhang

Yang

et al. 2015

Journal of the American Society of Nephrology

125

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Renal fibrosis is a final common manifestation of CKD resulting in progressive loss of kidney function. Bone marrow-derived fibroblast precursors contribute significantly to the pathogenesis of renal fibrosis. However, the signaling mechanisms underlying the activation of bone marrow-derived fibroblast precursors in the kidney are not fully understood. In this study, we investigated the role of the Janus kinase 3 (JAK3)/ signal transducer and activator of transcription (STAT6) signaling pathway in the activation of bone marrowderived fibroblasts. In cultured mouse monocytes, IL-4 or IL-13 activated STAT6 and induced expression of a-smooth muscle actin and extracellular matrix proteins (fibronectin and collagen I), which was abolished by a JAK3 inhibitor (CP690,550) in a dose-dependent manner or blocked in the absence of STAT6. In vivo, STAT6 was activated in interstitial cells of the obstructed kidney, an effect that was abolished by CP690,550. Mice treated with CP690,550 accumulated fewer bone marrow-derived fibroblasts in the obstructed kidneys compared with vehicle-treated mice. Treatment with CP690,550 also significantly reduced myofibroblast transformation, matrix protein expression, fibrosis development, and apoptosis in obstructed kidneys. Furthermore, STAT6-deficient mice accumulated fewer bone marrow-derived fibroblasts in the obstructed kidneys, produced less extracellular matrix protein, and developed much less fibrosis. Finally, wild-type mice engrafted with STAT6 2/2 bone marrow cells displayed fewer bone marrow-derived fibroblasts in the obstructed kidneys and showed less severe renal fibrosis compared with wild-type mice engrafted with STAT6 +/+ bone marrow cells. Our results demonstrate that JAK3/STAT6 has an important role in bone marrow-derived fibroblast activation, extracellular matrix production, and interstitial fibrosis development.

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STAT6 deficiency inhibits tubulointerstitial fibrosis in obstructive nephropathy

Cited by 12 publications

References 0 publications

Agonist-Driven Development of CD4+CD25+Foxp3+ Regulatory T Cells Requires a Second Signal Mediated by Stat6

Agonist-Driven Development of CD4+CD25+Foxp3+ Regulatory T Cells Requires a Second Signal Mediated by Stat6

Developmental signalling pathways in renal fibrosis: the roles of Notch, Wnt and Hedgehog

JAK3/STAT6 Stimulates Bone Marrow–Derived Fibroblast Activation in Renal Fibrosis

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