The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
권호 표지
DOI QR코드

DOI QR Code

Hydrogen sulfide, a gaseous signaling molecule, elongates primary cilia on kidney tubular epithelial cells by activating extracellular signal-regulated kinase

  • Han, Sang Jun (Department of Biotechnology, College of Fisheries Sciences, Pukyong National University) ;
  • Kim, Jee In (Department of Molecular Medicine, Keimyung University School of Medicine) ;
  • Lipschutz, Joshua H. (Department of Medicine, Medical University of South Carolina) ;
  • Park, Kwon Moo (Department of Anatomy, BK21 Plus, Cardiovascular Research Institute, School of Medicine, Kyungpook National University)
  • Received : 2021.07.20
  • Accepted : 2021.09.28
  • Published : 2021.11.01
Download PDF
⟨ Previous Next ⟩

Abstract

Primary cilia on kidney tubular cells play crucial roles in maintaining structure and physiological function. Emerging evidence indicates that the absence of primary cilia, and their length, are associated with kidney diseases. The length of primary cilia in kidney tubular epithelial cells depends, at least in part, on oxidative stress and extracellular signal-regulated kinase 1/2 (ERK) activation. Hydrogen sulfide (H2S) is involved in antioxidant systems and the ERK signaling pathway. Therefore, in this study, we investigated the role of H2S in primary cilia elongation and the downstream pathway. In cultured Madin-Darby Canine Kidney cells, the length of primary cilia gradually increased up to 4 days after the cells were grown to confluent monolayers. In addition, the expression of H2S-producing enzyme increased concomitantly with primary cilia length. Treatment with NaHS, an exogenous H2S donor, accelerated the elongation of primary cilia whereas DL-propargylglycine (a cystathionine γ-lyase inhibitor) and hydroxylamine (a cystathionine-β-synthase inhibitor) delayed their elongation. NaHS treatment increased ERK activation and Sec10 and Arl13b protein expression, both of which are involved in cilia formation and elongation. Treatment with U0126, an ERK inhibitor, delayed elongation of primary cilia and blocked the effect of NaHS-mediated primary cilia elongation and Sec10 and Arl13b upregulation. Finally, we also found that H2S accelerated primary cilia elongation after ischemic kidney injury. These results indicate that H2S lengthens primary cilia through ERK activation and a consequent increase in Sec10 and Arl13b expression, suggesting that H2S and its downstream targets could be novel molecular targets for regulating primary cilia.

Keywords

Acknowledgement

This work was supported by the Pukyong National University Research Fund in 2020 (CD20201553), the National Research Foundation Grant funded by the Korean Government (NRF-2020R1A2C2006903 to Park, K.M, NRF-2017R1A2A2A05069707 to Park, K.M., and NRF-2021R1C1C1003333 to Han, S.J.), Dialysis Clinic, Inc to Lipschutz, J.H. and the United States Department of Veterans Affairs (Merit Award I01 BX000820 to Lipschutz, J.H.).

References

  1. Badano JL, Mitsuma N, Beales PL, Katsanis N. The ciliopathies: an emerging class of human genetic disorders. Annu Rev Genomics Hum Genet. 2006;7:125-148. https://doi.org/10.1146/annurev.genom.7.080505.115610
  2. Bulger RE, Siegel FL, Pendergrass R. Scanning and transmission electron microscopy of the rat kidney. Am J Anat. 1974;139:483-501. https://doi.org/10.1002/aja.1001390403
  3. Webber WA, Lee J. Fine structure of mammalian renal cilia. Anat Rec. 1975;182:339-343. https://doi.org/10.1002/ar.1091820307
  4. Praetorius HA, Spring KR. The renal cell primary cilium functions as a flow sensor. Curr Opin Nephrol Hypertens. 2003;12:517-520. https://doi.org/10.1097/00041552-200309000-00006
  5. Praetorius HA, Spring KR. Removal of the MDCK cell primary cilium abolishes flow sensing. J Membr Biol. 2003;191:69-76. https://doi.org/10.1007/s00232-002-1042-4
  6. Zhang S, Pan C, Zhou F, Yuan Z, Wang H, Cui W, Zhang G. Hydrogen sulfide as a potential therapeutic target in fibrosis. Oxid Med Cell Longev. 2015;2015:593407. https://doi.org/10.1155/2015/593407
  7. Kim JI, Kim J, Jang HS, Noh MR, Lipschutz JH, Park KM. Reduction of oxidative stress during recovery accelerates normalization of primary cilia length that is altered after ischemic injury in murine kidneys. Am J Physiol Renal Physiol. 2013;304:F1283-F1294. https://doi.org/10.1152/ajprenal.00427.2012
  8. Wang S, Dong Z. Primary cilia and kidney injury: current research status and future perspectives. Am J Physiol Renal Physiol. 2013;305:F1085-F1098. https://doi.org/10.1152/ajprenal.00399.2013
  9. Jang HS, Han SJ, Kim JI, Lee S, Lipschutz JH, Park KM. Activation of ERK accelerates repair of renal tubular epithelial cells, whereas it inhibits progression of fibrosis following ischemia/reperfusion injury. Biochim Biophys Acta. 2013;1832:1998-2008. https://doi.org/10.1016/j.bbadis.2013.07.001
  10. Zuo X, Guo W, Lipschutz JH. The exocyst protein Sec10 is necessary for primary ciliogenesis and cystogenesis in vitro. Mol Biol Cell. 2009;20:2522-2529. https://doi.org/10.1091/mbc.E08-07-0772
  11. Fiorucci S, Distrutti E, Cirino G, Wallace JL. The emerging roles of hydrogen sulfide in the gastrointestinal tract and liver. Gastroenterology. 2006;131:259-271. https://doi.org/10.1053/j.gastro.2006.02.033
  12. Kimura H. Hydrogen sulfide: its production, release and functions. Amino Acids. 2011;41:113-121. https://doi.org/10.1007/s00726-010-0510-x
  13. Szabo C. Hydrogen sulphide and its therapeutic potential. Nat Rev Drug Discov. 2007;6:917-935. https://doi.org/10.1038/nrd2425
  14. Wang R. Two's company, three's a crowd: can H2S be the third endogenous gaseous transmitter? FASEB J. 2002;16:1792-1798. https://doi.org/10.1096/fj.02-0211hyp
  15. Banerjee R. Hydrogen sulfide: redox metabolism and signaling. Antioxid Redox Signal. 2011;15:339-341. https://doi.org/10.1089/ars.2011.3912
  16. Zhi L, Ang AD, Zhang H, Moore PK, Bhatia M. Hydrogen sulfide induces the synthesis of proinflammatory cytokines in human monocyte cell line U937 via the ERK-NF-kappaB pathway. J Leukoc Biol. 2007;81:1322-1332. https://doi.org/10.1189/jlb.1006599
  17. Cai WJ, Wang MJ, Ju LH, Wang C, Zhu YC. Hydrogen sulfide induces human colon cancer cell proliferation: role of Akt, ERK and p21. Cell Biol Int. 2010;34:565-572. https://doi.org/10.1042/CBI20090368
  18. Han SJ, Kim JI, Park JW, Park KM. Hydrogen sulfide accelerates the recovery of kidney tubules after renal ischemia/reperfusion injury. Nephrol Dial Transplant. 2015;30:1497-1506. https://doi.org/10.1093/ndt/gfv226
  19. Han SJ, Noh MR, Jung JM, Ishii I, Yoo J, Kim JI, Park KM. Hydrogen sulfide-producing cystathionine γ-lyase is critical in the progression of kidney fibrosis. Free Radic Biol Med. 2017;112:423-432. https://doi.org/10.1016/j.freeradbiomed.2017.08.017
  20. Asimakopoulou A, Panopoulos P, Chasapis CT, Coletta C, Zhou Z, Cirino G, Giannis A, Szabo C, Spyroulias GA, Papapetropoulos A. Selectivity of commonly used pharmacological inhibitors for cystathionine β synthase (CBS) and cystathionine γ lyase (CSE). Br J Pharmacol. 2013;169:922-932. https://doi.org/10.1111/bph.12171
  21. Jung KJ, Jang HS, Kim JI, Han SJ, Park JW, Park KM. Involvement of hydrogen sulfide and homocysteine transsulfuration pathway in the progression of kidney fibrosis after ureteral obstruction. Biochim Biophys Acta. 2013;1832:1989-1997. https://doi.org/10.1016/j.bbadis.2013.06.015
  22. Fan HN, Wang HJ, Yang-Dan CR, Ren L, Wang C, Li YF, Deng Y. Protective effects of hydrogen sulfide on oxidative stress and fibrosis in hepatic stellate cells. Mol Med Rep. 2013;7:247-253. https://doi.org/10.3892/mmr.2012.1153
  23. Zhu YZ, Wang ZJ, Ho P, Loke YY, Zhu YC, Huang SH, Tan CS, Whiteman M, Lu J, Moore PK. Hydrogen sulfide and its possible roles in myocardial ischemia in experimental rats. J Appl Physiol (1985). 2007;102:261-268. https://doi.org/10.1152/japplphysiol.00096.2006
  24. Han SJ, Jang HS, Noh MR, Kim J, Kong MJ, Kim JI, Park JW, Park KM. Mitochondrial NADP+-dependent isocitrate dehydrogenase deficiency exacerbates mitochondrial and cell damage after kidney ischemia-reperfusion injury. J Am Soc Nephrol. 2017;28:1200-1215. https://doi.org/10.1681/ASN.2016030349
  25. Larkins CE, Aviles GD, East MP, Kahn RA, Caspary T. Arl13b regulates ciliogenesis and the dynamic localization of Shh signaling proteins. Mol Biol Cell. 2011;22:4694-4703. https://doi.org/10.1091/mbc.E10-12-0994
  26. Seixas C, Choi SY, Polgar N, Umberger NL, East MP, Zuo X, Moreiras H, Ghossoub R, Benmerah A, Kahn RA, Fogelgren B, Caspary T, Lipschutz JH, Barral DC. Arl13b and the exocyst interact synergistically in ciliogenesis. Mol Biol Cell. 2016;27:308-320. https://doi.org/10.1091/mbc.E15-02-0061
  27. Verghese E, Ricardo SD, Weidenfeld R, Zhuang J, Hill PA, Langham RG, Deane JA. Renal primary cilia lengthen after acute tubular necrosis. J Am Soc Nephrol. 2009;20:2147-2153. https://doi.org/10.1681/ASN.2008101105
  28. Wang L, Weidenfeld R, Verghese E, Ricardo SD, Deane JA. Alterations in renal cilium length during transient complete ureteral obstruction in the mouse. J Anat. 2008;213:79-85. https://doi.org/10.1111/j.1469-7580.2008.00918.x
  29. Keeling J, Tsiokas L, Maskey D. Cellular mechanisms of ciliary length control. Cells. 2016;5:6. https://doi.org/10.3390/cells5010006
  30. Avasthi P, Marshall WF. Stages of ciliogenesis and regulation of ciliary length. Differentiation. 2012;83:S30-S42. https://doi.org/10.1016/j.diff.2011.11.015
  31. Han SJ, Jung JK, Im SS, Lee SR, Jang BC, Park KM, Kim JI. Deficiency of primary cilia in kidney epithelial cells induces epithelial to mesenchymal transition. Biochem Biophys Res Commun. 2018;496:450-454. https://doi.org/10.1016/j.bbrc.2018.01.079
  32. Han SJ, Jang HS, Kim JI, Lipschutz JH, Park KM. Unilateral nephrectomy elongates primary cilia in the remaining kidney via reactive oxygen species. Sci Rep. 2016;6:22281. https://doi.org/10.1038/srep22281
  33. Lipschutz JH, Guo W, O'Brien LE, Nguyen YH, Novick P, Mostov KE. Exocyst is involved in cystogenesis and tubulogenesis and acts by modulating synthesis and delivery of basolateral plasma membrane and secretory proteins. Mol Biol Cell. 2000;11:4259-4275. https://doi.org/10.1091/mbc.11.12.4259
  34. Park KM, Fogelgren B, Zuo X, Kim J, Chung DC, Lipschutz JH. Exocyst Sec10 protects epithelial barrier integrity and enhances recovery following oxidative stress, by activation of the MAPK pathway. Am J Physiol Renal Physiol. 2010;298:F818-F826. https://doi.org/10.1152/ajprenal.00596.2009
  35. Yang G, Sun X, Wang R. Hydrogen sulfide-induced apoptosis of human aorta smooth muscle cells via the activation of mitogen-activated protein kinases and caspase-3. FASEB J. 2004;18:1782-1784. https://doi.org/10.1096/fj.04-2279fje
  36. Liu D, Wang Z, Zhan J, Zhang Q, Wang J, Zhang Q, Xian X, Luan Q, Hao A. Hydrogen sulfide promotes proliferation and neuronal differentiation of neural stem cells and protects hypoxia-induced decrease in hippocampal neurogenesis. Pharmacol Biochem Behav. 2014;116:55-63. https://doi.org/10.1016/j.pbb.2013.11.009
  37. Choi DE, Jeong JY, Choi H, Chang YK, Ahn MS, Ham YR, Na KR, Lee KW. ERK phosphorylation plays an important role in the protection afforded by hypothermia against renal ischemia-reperfusion injury. Surgery. 2017;161:444-452. https://doi.org/10.1016/j.surg.2016.07.028