Regulation of KLF12 by microRNA‐20b and microRNA‐106a in cystogenesis

Shin, Yubin; Kim, Do Yeon; Ko, Je Yeong; Woo, Yu Mi; Park, Jong Hoon

doi:10.1096/fj.201700923r

Cited by 18 publications

(6 citation statements)

References 16 publications

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“…We suggested that this difference may be related to their phenotypic differences. Furthermore, we observed decreased expression of miR-20b-5p and miR-106a-5p and up-regulation of its target KLF12 in Pkd2 f/f :HoxB7-Cre mice compared with Pkd2 f/f control mice (41). In addition, these findings were highly similar in a human cell line, mouse cell lines, and Pkd2 KO mouse embryonic fibroblasts.…”

Section: Discussionsupporting

confidence: 65%

Impact of miR‐192 and miR‐194 on cyst enlargement through EMT in autosomal dominant polycystic kidney disease

et al. 2018

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Altered miRNA (miR) expression occurs in various diseases. However, the therapeutic effect of miRNAs in autosomal dominant polycystic kidney disease (ADPKD) is unclear. Genome‐wide analyses of miRNA expression and DNA methylation status were conducted to identify crucial miRNAs in end‐stage ADPKD. miR‐192 and ‐194 levels were down‐regulated with hypermethylation at these loci, mainly in the intermediate and late stages, not in the early stage, of cystogenesis, suggesting their potential impact on cyst expansion. Cyst expansion has been strongly associated with endothelial‐mesenchymal transition (EMT). Zinc finger E‐box‐binding homeobox‐2 and cadherin‐2, which are involved in EMT, were directly regulated by miR‐192 and ‐194. The therapeutic effect of miR‐192 and ‐194 in vivo and in vitro were assessed. Restoring these miRs by injection of precursors influenced the reduced size of cysts in Pkd1 conditional knockout mice. miR‐192 and ‐194 may act as potential therapeutic targets to control the expansion and progression of cysts in patients with ADPKD.—Kim, D. Y., Woo, Y. M., Lee, S., Oh, S., Shin, Y., Shin, J.‐O., Park, E. Y., Ko, J. Y., Lee, E. J., Bok, J., Yoo, K. H., Park, J. H. Impact of miR‐192 and miR‐194 on cyst enlargement through EMT in autosomal dominant polycystic kidney disease. FASEB J. 33, 2870–2884 (2019). http://www.fasebj.org

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Section: Discussionsupporting

confidence: 65%

Impact of miR‐192 and miR‐194 on cyst enlargement through EMT in autosomal dominant polycystic kidney disease

et al. 2018

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“…Conversely, downregulation of KLF12 resulted in a proliferative defect in multiple cancer cell lines (19,23,(44)(45)(46)(47). These observations were recapitulated in primary human cancer cells and mouse kidney cells (48,49). In this study, we observed a proliferative defect in KLF12-deficient NK cells in a competitive setting in BM chimeric mice upon Ag-and cytokine-mediated proliferation.…”

Section: Discussionsupporting

confidence: 60%

KLF12 Regulates Mouse NK Cell Proliferation

Lam

Folkersen

Aguilar

et al. 2019

The Journal of Immunology

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NK cells are innate lymphocytes that play an integral role in tumor rejection and viral clearance. Unlike their other lymphocyte counterparts, NK cells have the unique ability to recognize and lyse target cells without prior exposure. However, there are no known NK cell-specific genes that are exclusively expressed by all NK cells. Therefore, identification of NK cell-specific genes would allow a better understanding of why NK cells are unique cytotoxic lymphocytes. From the Immunological Genome (ImmGen) Consortium studies, we identified kruppel-like factor 12 (Klf12), encoding a novel transcription factor, preferentially expressed in C57BL/6 mouse NK cells. KLF12 was dispensable for NK cell development, IFN-γ production, degranulation, and proliferation in Klf12 knockout mice. RNA-sequencing analysis revealed increased expression of Btg3, an antiproliferative gene, in KLF12-deficient NK cells compared with wild-type NK cells. Interestingly, competitive mixed bone marrow chimeric mice exhibited reduced development of KLF12-deficient NK cells, altered IFN-γ production and degranulation, and impairment of NK cell proliferation in vitro and in vivo in response to mouse CMV infection. KLF12-deficient NK cells from bone marrow chimeric mice also expressed higher levels of the IL-21R, which resulted in increased IL-21R signaling and correlated with greater inhibition of NK cell proliferation. Furthermore, IL-21 induced Btg3 expression, which correlated with arrested NK cell maturation and proliferation. In summary, we found that KLF12 regulates mouse NK cell proliferation potentially by regulating expression of Btg3 via IL-21.

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“…Outside of the miR-17–92 cluster, several other miRNAs have been associated with PKD. These include miR-21 [61], miR-20b-5p and miR-106a-5p [62], miR-199a-5p [63] and miR-501-5p [64] and suggest that targeting miRNAs pharmacologically may represent a new paradigm in PKD treatment [50].…”

Section: Molecular Targets On the Horizonmentioning

confidence: 99%

Emerging targeted strategies for the treatment of autosomal dominant polycystic kidney disease

Weimbs

Shillingford

Torres

et al. 2018

Clinical Kidney Journal

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Autosomal dominant polycystic kidney disease (ADPKD) is a widespread genetic disease that leads to renal failure in the majority of patients. The very first pharmacological treatment, tolvaptan, received Food and Drug Administration approval in 2018 after previous approval in Europe and other countries. However, tolvaptan is moderately effective and may negatively impact a patient’s quality of life due to potentially significant side effects. Additional and improved therapies are still urgently needed, and several clinical trials are underway, which are discussed in the companion paper Müller and Benzing (Management of autosomal-dominant polycystic kidney disease—state-of-the-art) Clin Kidney J 2018; 11: i2–i13. Here, we discuss new therapeutic avenues that are currently being investigated at the preclinical stage. We focus on mammalian target of rapamycin and dual kinase inhibitors, compounds that target inflammation and histone deacetylases, RNA-targeted therapeutic strategies, glucosylceramide synthase inhibitors, compounds that affect the metabolism of renal cysts and dietary restriction. We discuss tissue targeting to renal cysts of small molecules via the folate receptor, and of monoclonal antibodies via the polymeric immunoglobulin receptor. A general problem with potential pharmacological approaches is that the many molecular targets that have been implicated in ADPKD are all widely expressed and carry out important functions in many organs and tissues. Because ADPKD is a slowly progressing, chronic disease, it is likely that any therapy will have to continue over years and decades. Therefore, systemically distributed drugs are likely to lead to potentially prohibitive extra-renal side effects during extended treatment. Tissue targeting to renal cysts of such drugs is one potential way around this problem. The use of dietary, instead of pharmacological, interventions is another.

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Regulation of KLF12 by microRNA‐20b and microRNA‐106a in cystogenesis

Cited by 18 publications

References 16 publications

Impact of miR‐192 and miR‐194 on cyst enlargement through EMT in autosomal dominant polycystic kidney disease

Impact of miR‐192 and miR‐194 on cyst enlargement through EMT in autosomal dominant polycystic kidney disease

KLF12 Regulates Mouse NK Cell Proliferation

Emerging targeted strategies for the treatment of autosomal dominant polycystic kidney disease

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