Browse > Article
http://dx.doi.org/10.4062/biomolther.2020.197

Suppression of Foxo3-Gatm by miR-132-3p Accelerates Cyst Formation by Up-Regulating ROS in Autosomal Dominant Polycystic Kidney Disease  

Choi, Seonju (Department of Biological Sciences and Research Institute of Women's Health, Sookmyung Women's University)
Kim, Do Yeon (Department of Biological Sciences and Research Institute of Women's Health, Sookmyung Women's University)
Ahn, Yejin (Department of Biological Sciences and Research Institute of Women's Health, Sookmyung Women's University)
Lee, Eun Ji (Department of Biological Sciences and Research Institute of Women's Health, Sookmyung Women's University)
Park, Jong Hoon (Department of Biological Sciences and Research Institute of Women's Health, Sookmyung Women's University)
Publication Information
Biomolecules & Therapeutics / v.29, no.3, 2021 , pp. 311-320 More about this Journal
Abstract
Accumulation of reactive oxygen species (ROS) is associated with the development of various diseases. However, the molecular mechanisms underlying oxidative stress that lead to such diseases like autosomal dominant polycystic kidney disease (ADPKD) remain unclear. Here, we observed that oxidative stress markers were increased in Pkd1f/f:HoxB7-Cre mice. Forkhead transcription factors of the O class (FOXOs) are known key regulators of the oxidative stress response, which have been observed with the expression of FoxO3a in an ADPKD mouse model in the present study. An integrated analysis of two datasets for differentially expressed miRNA, such as miRNA sequencing analysis of Pkd1 conditional knockout mice and microarray analysis of samples from ADPKD patients, showed that miR-132-3p was a key regulator of FOXO3a in ADPKD. miR-132-3p was significantly upregulated in ADPKD which directly targeted FOXO3 in both mouse and human cell lines. Interestingly, the mitochondrial gene Gatm was downregulated in ADPKD which led to a decreased inhibition of Foxo3. Overexpression of miR-132-3p coupled with knockdown of Foxo3 and Gatm increased ROS and accelerated cyst formation in 3D culture. This study reveals a novel mechanism involving miR-132-3p, Foxo3, and Gatm that is associated with the oxidative stress that occurs during cystogenesis in ADPKD.
Keywords
ADPKD; FOXO3; ROS; MicroRNA; Cystogenesis;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Ham, H. J., Park, J. W. and Bae, Y. S. (2019) Defect of SIRT1-FoxO3a axis is associated with the production of reactive oxygen species during protein kinase CK2 downregulation-mediated cellular senescence and nematode aging. BMB Rep. 52, 265-270.   DOI
2 Humm, A., Fritsche, E., Steinbacher, S. and Huber, R. (1997) Crystal structure and mechanism of human L-arginine:glycine amidinotransferase: a mitochondrial enzyme involved in creatine biosynthesis. EMBO J. 16, 3373-3385.   DOI
3 Igarashi, P. and Somlo, S. (2007) Polycystic kidney disease. J. Am. Soc. Nephrol. 18, 1371-1373.   DOI
4 Ishimoto, Y., Inagi, R., Yoshihara, D., Kugita, M., Nagao, S., Shimizu, A., Takeda, N., Wake, M., Honda, K., Zhou, J. and Nangaku, M. (2017) Mitochondrial abnormality facilitates cyst formation in autosomal dominant polycystic kidney disease. Mol. Cell. Biol. 37, e00337-17.
5 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. and Park, J. H. (2019) Impact of miR-192 and miR-194 on cyst enlargement through EMT in autosomal dominant polycystic kidney disease. FASEB J. 33, 2870-2884..   DOI
6 Li, L., Kang, H., Zhang, Q., D'Agati, V. D., Al-Awqati, Q. and Lin, F. (2019) FoxO3 activation in hypoxic tubules prevents chronic kidney disease. J. Clin. Invest. 129, 2374-2389.   DOI
7 Li, Y., Li, J., Woo, Y. M., Shen, Z., Yao, H., Cai, Y., Lin, M. C. and Poon, W. S. (2017) Enhanced expression of Vastatin inhibits angiogenesis and prolongs survival in murine orthotopic glioblastoma model. BMC Cancer 17, 126.   DOI
8 Woo, Y. M., Kim, D. Y., Koo, N. J., Kim, Y. M., Lee, S., Ko, J. Y., Shin, Y., Kim, B. H., Mun, H., Choi, S., Lee, E. J., Shin, J. O., Park, E. Y., Bok, J. and Park, J. H. (2017) Profiling of miRNAs and target genes related to cystogenesis in ADPKD mouse models. Sci. Rep. 7, 14151.   DOI
9 Reichold, M., Klootwijk, E. D., Reinders, J., Otto, E. A., Milani, M., Broeker, C., Laing, C., Wiesner, J., Devi, S., Zhou, W., Schmitt, R., Tegtmeier, I., Sterner, C., Doellerer, H., Renner, K., Oefner, P. J., Dettmer, K., Simbuerger, J. M., Witzgall, R., Stanescu, H. C., Dumitriu, S., Iancu, D., Patel, V., Mozere, M., Tekman, M., Jaureguiberry, G., Issler, N., Kesselheim, A., Walsh, S. B., Gale, D. P., Howie, A. J., Martins, J. R., Hall, A. M., Kasgharian, M., O'Brien, K., Ferreira, C. R., Atwal, P. S., Jain, M., Hammers, A., Charles-Edwards, G., Choe, C. U., Isbrandt, D., Cebrian-Serrano, A., Davies, B., Sandford, R. N., Pugh, C., Konecki, D. S., Povey, S., Bockenhauer, D., Lichter-Konecki, U., Gahl, W. A., Unwin, R. J., Warth, R. and Kleta, R. (2018) Glycine amidinotransferase (GATM), renal fanconi syndrome, and kidney failure. J. Am. Soc. Nephrol. 29, 1849-1858.   DOI
10 Andries, A., Daenen, K., Jouret, F., Bammens, B., Mekahli, D. and Van Schepdael, A. (2019) Oxidative stress in autosomal dominant polycystic kidney disease: player and/or early predictor for disease progression? Pediatr. Nephrol. 34, 993-1008.   DOI
11 Zhang, J., Wang, X., Vikash, V., Ye, Q., Wu, D., Liu, Y. and Dong, W. (2016) ROS and ROS-mediated cellular signaling. Oxid. Med. Cell. Longev. 2016, 4350965.   DOI
12 Marinkovic, D., Zhang, X., Yalcin, S., Luciano, J. P., Brugnara, C., Huber, T. and Ghaffari, S. (2007) Foxo3 is required for the regulation of oxidative stress in erythropoiesis. J. Clin. Invest. 117, 2133-2144.   DOI
13 Kim, J. E., Hong, J. W., Lee, H. S., Kim, W., Lim, J., Cho, Y. S. and Kwon, H. J. (2018) Hsa-miR-10a-5p downregulation in mutant UQCRB-expressing cells promotes the cholesterol biosynthesis pathway. Sci. Rep. 8, 12407.   DOI
14 Klotz, L. O., Sanchez-Ramos, C., Prieto-Arroyo, I., Urbanek, P., Steinbrenner, H. and Monsalve, M. (2015) Redox regulation of FoxO transcription factors. Redox Biol. 6, 51-72.   DOI
15 Kops, G. J., Dansen, T. B., Polderman, P. E., Saarloos, I., Wirtz, K. W., Coffer, P. J., Huang, T. T., Bos, J. L., Medema, R. H. and Burgering, B. M. (2002) Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature 419, 316-321.   DOI
16 Lin, F. (2020) Molecular regulation and function of FoxO3 in chronic kidney disease. Curr. Opin. Nephrol. Hypertens 29, 439-445.   DOI
17 Liu, J. W., Chandra, D., Rudd, M. D., Butler, A. P., Pallotta, V., Brown, D., Coffer, P. J. and Tang, D. G. (2005) Induction of prosurvival molecules by apoptotic stimuli: involvement of FOXO3a and ROS. Oncogene 24, 2020-2031.   DOI
18 Mochizuki, T., Wu, G., Hayashi, T., Xenophontos, S.L., Veldhuisen, B., Saris, J. J., Reynolds, D. M., Cai, Y., Gabow, P. A., Pierides, A., Kimberling, W. J., Breuning, M. H., Deltas, C. C., Peters, D. J. and Somlo, S. (1996) PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science 272, 1339-1342.   DOI
19 Peters, D. J. and Sandkuijl, L. A. (1992) Genetic heterogeneity of poly-cystic kidney disease in Europe. Contrib. Nephrol. 97, 128-139.   DOI
20 Torres, V. E., Chapman, A. B., Devuyst, O., Gansevoort, R. T., Grantham, J. J., Higashihara, E., Perrone, R. D., Krasa, H. B., Ouyang, J. and Czerwiec, F. S.; TEMPO 3:4 Trial Investigators (2012) Tolvaptan in patients with autosomal dominant polycystic kidney disease. N. Engl. J. Med. 367, 2407-2418.   DOI
21 Tzivion, G., Dobson, M. and Ramakrishnan, G. (2011) FoxO transcription factors; regulation by AKT and 14-3-3 proteins. Biochim. Biophys. Acta 1813, 1938-1945.   DOI
22 van der Horst, A. and Burgering, B. M. (2007) Stressing the role of FoxO proteins in lifespan and disease. Nat. Rev. Mol. Cell Biol. 8, 440-450.   DOI
23 Woo, Y. M., Bae, J. B., Oh, Y. H., Lee, Y. G., Lee, M. J., Park, E. Y., Choi, J. K., Lee, S., Shin, Y., Lyu, J., Jung, H. Y., Lee, Y. S., Hwang, Y. H., Kim, Y. J. and Park, J. H. (2014) Genome-wide methylation profiling of ADPKD identified epigenetically regulated genes associated with renal cyst development. Hum. Genet. 133, 281-297.   DOI
24 Ferber, E. C., Peck, B., Delpuech, O., Bell, G. P., East, P. and Schulze, A. (2012) FOXO3a regulates reactive oxygen metabolism by inhibiting mitochondrial gene expression. Cell Death Differ. 19, 968-979.   DOI
25 Bijkerk, R., de Bruin, R. G., van Solingen, C., van Gils, J. M., Duijs, J. M., van der Veer, E. P., Rabelink, T. J., Humphreys, B. D. and van Zonneveld, A. J. (2016) Silencing of microRNA-132 reduces renal fibrosis by selectively inhibiting myofibroblast proliferation. Kidney Int. 89, 1268-1280.   DOI
26 Calnan, D. R. and Brunet, A. (2008) The FoxO code. Oncogene 27, 2276-2288.   DOI
27 Calvo, S. E., Clauser, K. R. and Mootha, V. K. (2016) MitoCarta2.0: an updated inventory of mammalian mitochondrial proteins. Nucleic Acids Res. 44, D1251-D1257.   DOI
28 Hagenbuchner, J., Kuznetsov, A., Hermann, M., Hausott, B., Obexer, P. and Ausserlechner, M. J. (2012) FOXO3-induced reactive oxygen species are regulated by BCL2L11 (Bim) and SESN3. J. Cell Sci. 125, 1191-1203.   DOI
29 Fujiki, T., Ando, F., Murakami, K., Isobe, K., Mori, T., Susa, K., Nomura, N., Sohara, E., Rai, T. and Uchida, S. (2019) Tolvaptan activates the Nrf2/HO-1 antioxidant pathway through PERK phosphorylation. Sci. Rep. 9, 9245.   DOI
30 Gansevoort, R. T., Arici, M., Benzing, T., Birn, H., Capasso, G., Covic, A., Devuyst, O., Drechsler, C., Eckardt, K. U., Emma, F., Knebelmann, B., Le Meur, Y., Massy, Z. A., Ong, A. C., Ortiz, A., Schaefer, F., Torra, R., Vanholder, R., Wiecek, A., Zoccali, C. and Van Biesen, W. (2016) Recommendations for the use of tolvaptan in autosomal dominant polycystic kidney disease: a position statement on behalf of the ERA-EDTA Working Groups on Inherited Kidney Disorders and European Renal Best Practice. Nephrol. Dial. Transplant. 31, 337-348.   DOI