Reducing Inflammatory Cytokine Production from Renal Collecting Duct Cells by Inhibiting GATA2 Ameliorates Acute Kidney Injury

Yu, Li; Moriguchi, Takashi; Kaneko, Hiroshi; Hayashi, Makiko; Hasegawa, Atsushi; Nezu, Masahiro; Saya, Hideyuki; Yamamoto, Masayuki; Shimizu, Ritsuko

doi:10.1128/mcb.00211-17

Cited by 24 publications

(24 citation statements)

References 50 publications

(58 reference statements)

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“…f). A very recent study has shown that GATA2 induces inflammatory cytokine genes during the pathogenesis of acute kidney injury . In the current study, however, we deduced that GATA2 exerts no regulatory effects on the proinflammatory response in synovial cells on the basis of the following three pieces of evidence: (i) the strength of expression of GATA2 was equally low in OA and RA clinical tissue samples (Fig.…”

Section: Resultsmentioning

confidence: 56%

Synovial GATA1 mediates rheumatoid arthritis progression via transcriptional activation of NOS2 signaling

Liu¹,

Wei²,

Zhi³

et al. 2018

Microbiology and Immunology

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Transcriptional regulation of inducible nitric oxide synthase (iNOS) is critically involved in the pathogenesis and progression of rheumatoid arthritis (RA); however, the specific transcription factors that control this process remain largely unidentified. In the present study, it was discovered that expression of the key erythroid factor, globin transcription factor 1 (GATA1), is significantly greater in human RA synovial tissues than in osteoarthritis (OA) tissues. IL 6 was found to induce synovial GATA1 expression in a signal transducer and activator of transcription 3-dependent manner. Functionally, knockdown of GATA1 expression using specific small interfering RNA treatment was found to compromise immunoreaction-elicited expression of proinflammatory cytokines and thus impair invasiveness of the human fibroblast-like synovial cell line MH7A, whereas introduction of exogenous GATA1 was found to promote production of proinflammatory cytokines, leading to greater aggressiveness of MH7A cells. Mechanistically, GATA1 acts as the transcriptional coactivator of NOS2 (the gene encoding iNOS) transcription. Collectively, these data suggest that synovial GATA1 is an essential contributor to development and exacerbation of RA, presumably by inducing NOS2 transcription.

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Section: Resultsmentioning

confidence: 56%

Synovial GATA1 mediates rheumatoid arthritis progression via transcriptional activation of NOS2 signaling

Liu¹,

Wei²,

Zhi³

et al. 2018

Microbiology and Immunology

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“…Emerging studies suggest that the CD of the kidney may function as an essential regulator of inflammation in response to renal injury in addition to transporting water and salt. 37,62,63 Why is CD injury "inflammatory?" It could be due to PC necroptosis, which is known to be highly inflammatory in general.…”

Section: Discussionmentioning

confidence: 99%

Integrin-Linked Kinase Deficiency in Collecting Duct Principal Cell Promotes Necroptosis of Principal Cell and Contributes to Kidney Inflammation and Fibrosis

Huang

Zhu

Huang

et al. 2019

JASN

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BackgroundNecroptosis is a newly discovered cell death pathway that plays a critical role in AKI. The involvement of integrin-linked kinase (ILK) in necroptosis has not been studied.MethodsWe performed experiments in mice with an Ilk deletion in collecting duct (CD) principal cells (PCs), and cultured tubular epithelial cells treated with an ILK inhibitor or ILK siRNA knockdown.ResultsIlk deletion in CD PCs resulted in acute tubular injury and early mortality in mice. Progressive interstitial fibrosis and inflammation associated with the activation of the canonical TGF-β signaling cascade were detected in the kidneys of the mice lacking ILK in the CD PCs. In contrast to the minimal apoptosis detected in the animals’ injured CDs, widespread necroptosis was present in ILK-deficient PCs, characterized by cell swelling, deformed mitochondria, and rupture of plasma membrane. In addition, ILK deficiency resulted in increased expression and activation of necroptotic proteins MLKL and RIPK3, and membrane translocation of MLKL in CD PCs. ILK inhibition and siRNA knockdown reduced cell survival in cultured tubular cells, concomitant with increased membrane accumulation of MLKL and/or phospho-MLKL. Administration of a necroptosis inhibitor, necrostatin-1, blocked cell death in vitro and significantly attenuated inflammation, interstitial fibrosis, and renal failure in ILK-deficient mice.ConclusionsThe study demonstrates the critical involvement of ILK in necroptosis through modulation of the RIPK3 and MLKL pathway and highlights the contribution of CD PC injury to the development of inflammation and interstitial fibrosis of the kidney.

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“…For instance, GATA3 is involved in Th2 gene expression in response to allergic stimuli and exposure to air pollution (Dong & Ma, 2016;Maneechotesuwan et al, 2007). GATA2 promotes the expression of proinflammatory cytokines in collecting duct cells in response to kidney injury (Yu et al, 2017). GATA4 and GATA5 regulate BCL2L1 gene expression against cardiotoxic agents and hypoxic stimuli, respectively (Aries, Paradis, Lefebvre, Schwartz, & Nemer, 2004;Wu, Wang, Lin, Liu, & Chen, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…We have identified two GATA inhibitors, K-7174 (Umetani et al, 2000) and mitoxantrone (Yu et al, 2017). Mitoxantrone was isolated in our recent high-throughput screenings of GATA inhibitors using an off-patent chemical library.…”

mentioning

confidence: 99%

Induction of erythropoietin gene expression in epithelial cells by chemicals identified in GATA inhibitor screenings

et al. 2017

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Erythropoietin (EPO) is a hormone that promotes proliferation, differentiation and survival of erythroid progenitors. EPO gene expression is regulated in a tissue-specific and hypoxia-inducible manner and is mainly restricted to renal EPO-producing cells after birth. Chronic kidney disease (CKD) confers high risk for renal anemia due to lower EPO production from injured kidneys. In transgenic reporter lines of mice, disruption of a GATA-binding motif within the Epo gene promoter-proximal region restores constitutive reporter expression in epithelial cells. Here, mitoxantrone and its analogues, identified as GATA factor inhibitors through high-throughput chemical library screenings, markedly induce EPO/Epo gene expression in epithelium-derived cell lines and mice regardless of oxygen levels. In contrast, mitoxantrone interferes with hypoxia-induced EPO gene expression in Hep3B cells. Cryptic promoters are created for the EPO/Epo gene expression in epithelial cells upon mitoxantrone treatment, and consequently, unique 5'-untranslated regions are generated. The mitoxantrone-induced aberrant transcripts contribute to the reporter protein production in epithelial cells that carry the reporter gene in the proper reading frame of mouse Epo gene. Thus, EPO production in uninjured adult epithelial cells may be a therapeutic approach for renal anemia in patients with CKD.

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Reducing Inflammatory Cytokine Production from Renal Collecting Duct Cells by Inhibiting GATA2 Ameliorates Acute Kidney Injury

Cited by 24 publications

References 50 publications

Synovial GATA1 mediates rheumatoid arthritis progression via transcriptional activation of NOS2 signaling

Synovial GATA1 mediates rheumatoid arthritis progression via transcriptional activation of NOS2 signaling

Integrin-Linked Kinase Deficiency in Collecting Duct Principal Cell Promotes Necroptosis of Principal Cell and Contributes to Kidney Inflammation and Fibrosis

Induction of erythropoietin gene expression in epithelial cells by chemicals identified in GATA inhibitor screenings

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