The Korean Journal of Physiology and Pharmacology

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

DOI QR Code

Regulator of Calcineurin 1 Isoform 4 (RCAN1.4) Is Overexpressed in the Glomeruli of Diabetic Mice

  • Jang, Cho-Rong (Department of Pharmacology, College of Medicine, The Catholic University of Korea) ;
  • Lim, Ji-Hee (Depratment of Internal Medicine, College of Medicine, The Catholic University of Korea) ;
  • Park, Cheol-Whee (Depratment of Internal Medicine, College of Medicine, The Catholic University of Korea) ;
  • Cho, Young-Jin (Department of Pharmacology, College of Medicine, The Catholic University of Korea)
  • Received : 2011.09.16
  • Accepted : 2011.10.21
  • Published : 2010.10.30
Download PDF
⟨ Previous Next ⟩

Abstract

Calcineurin (CaN) is activated in diabetes and plays a role in glomerular hypertrophy and extracellular matrix (ECM) accumulation. Here, kidneys from diabetic model mice were investigated for the expression of the regulator of CaN 1 (RCAN1) isoform 4 (RCAN1.4) which had been shown to be transcriptionally upregulated by CaN activation. We found the increased immunoreactivity for RCAN1 in the glomerular cells of db/db mice and streptozotocin-induced diabetic mice. In concordance, the expression of RCAN1 protein and RCAN1.4 mRNA were elevated in the whole kidney sample from db/db mice. Interleukin-$1{\beta}$ (IL-$1{\beta}$), tumor necrosis factor-${\alpha}$, and glycated albumin (AGE-BSA) were identified as inducers of RCAN1.4 in mesangial cells. Pretreatment of cyclosporine A blocked the increases of RCAN1.4 stimulated by IL-$1{\beta}$ or AGE-BSA, suggesting that activation of CaN is required for the RCAN1.4 induction. Stable transfection of RCAN1.4 in Mes-13 mesangial cells upregulated several factors relevant to ECM production and degradation. These results suggested that RCAN1.4 might act as a link between CaN activation and ECM turnover in diabetic nephropathy.

Keywords

References

  1. Iidaka K, McCoy J, Kimmelstiel P. The glomerular mesangium: a quantitative analy-sis. Lab Invest. 1968;19:573-579.
  2. Kawano K, Arakawa M, McCoy J, Porch J, Kimmelstiel P. Quantitative study of glomeruli. Focal glomerulonephritis and diabetic glomerulosclerosis. Lab Invest. 1969;21:269-275.
  3. Ayo SH, Radnik RA, Garoni JA, Glass WF 2nd, Kreisberg JI. High glucose causes an increase in extracellular matrix proteins in cultured mesangial cells. Am J Pathol. 1990;136: 1339-1348.
  4. Doi T, Vlassara H, Kirstein M, Yamada Y, Striker GE, Striker LJ. Receptor-specific increase in extracellular matrix production in mouse mesangial cells by advanced glycosylation end products is mediated via platelet-derived growth factor. Proc Natl Acad Sci USA. 1992;89:2873-2877. https://doi.org/10.1073/pnas.89.7.2873
  5. Mason RM, Wahab NA. Extracellular matrix metabolism in diabetic nephropathy. J Am Soc Nephrol. 2003;14:1358-1373. https://doi.org/10.1097/01.ASN.0000065640.77499.D7
  6. Flyvbjerg A. Putative pathophysiological role of growth factors and cytokines in experimental diabetic kidney disease. Diabetologia. 2000;43:1205-1223. https://doi.org/10.1007/s001250051515
  7. Chiarelli F, Gaspari S, Marcovecchio ML. Role of growth factors in diabetic kidney disease. Horm Metab Res. 2009;41:585-593. https://doi.org/10.1055/s-0029-1220752
  8. Blazquez-Medela AM, Lopez-Novoa JM, Martinez-Salgado C. Mechanisms involved in the genesis of diabetic nephropathy. Curr Diabetes Rev. 2010;6:68-87. https://doi.org/10.2174/157339910790909422
  9. Grønbaek H, Volmers P, Bjørn SF, Osterby R, Orskov H, Flyvbjerg A. Effect of GH/IGF-I deficiency on long-term renal changes and urinary albumin excretion in diabetic dwarf rats. Am J Physiol. 1997;272:E918-924.
  10. Gooch JL, Barnes JL, Garcia S, Abboud HE. Calcineurin is activated in diabetes and is required for glomerular hypertrophy and ECM accumulation. Am J Physiol Renal Physiol. 2003;284:F144-154. https://doi.org/10.1152/ajprenal.00158.2002
  11. Gooch JL, Tang Y, Ricono JM, Abboud HE. Insulin-like growth factor-I induces renal cell hypertrophy via a calcineurindependent mechanism. J Biol Chem. 2001;276:42492-42500. https://doi.org/10.1074/jbc.M102994200
  12. Gooch JL, Gorin Y, Zhang BX, Abboud HE. Involvement of calcineurin in transforming growth factor-beta-mediated regulation of extracellular matrix accumulation. J Biol Chem. 2004;279:15561-15570. https://doi.org/10.1074/jbc.M308759200
  13. Rothermel BA, Vega RB, Williams RS. The role of modulatory calcineurin-interacting proteins in calcineurin signaling. Trends Cardiovasc Med. 2003;13:15-21. https://doi.org/10.1016/S1050-1738(02)00188-3
  14. Fuentes JJ, Genesca L, Kingsbury TJ, Cunningham KW, Perez-Riba M, Estivill X, de la Luna S. DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways. Hum Mol Genet. 2000;9:1681-1690. https://doi.org/10.1093/hmg/9.11.1681
  15. Fuentes JJ, Pritchard MA, Planas AM, Bosch A, Ferrer I, Estivill X. A new human gene from the Down syndrome critical region encodes a proline-rich protein highly expressed in fetal brain and heart. Hum Mol Genet. 1995;4:1935-1944. https://doi.org/10.1093/hmg/4.10.1935
  16. Fuentes JJ, Pritchard MA, Estivill X. Genomic organization, alternative splicing, and expression patterns of the DSCR1 (Down syndrome candidate region 1) gene. Genomics. 1997;44: 358-361. https://doi.org/10.1006/geno.1997.4866
  17. Abe M, Sato Y. cDNA microarray analysis of the gene expression profile of VEGF-activated human umbilical vein endothelial cells. Angiogenesis. 2001;4:289-298. https://doi.org/10.1023/A:1016018617152
  18. Mann KM, Ray JL, Moon ES, Sass KM, Benson MR. Calcineurin initiates smooth muscle differentiation in neural crest stem cells. J Cell Biol. 2004;165:483-491.25. https://doi.org/10.1083/jcb.200402105
  19. Cho KO, Kim YS, Cho YJ, Kim SY. Upregulation of DSCR1 (RCAN1 or Adapt78) in the peri-infarct cortex after experimental stroke. Exp Neurol. 2008;212:85-92. https://doi.org/10.1016/j.expneurol.2008.03.017
  20. Crawford DR, Leahy KP, Abramova N, Lan L, Wang Y, Davies KJ. Hamster adapt78 mRNA is a Down syndrome critical region homologue that is inducible by oxidative stress. Arch Biochem Biophys. 1997;342:6-12. https://doi.org/10.1006/abbi.1997.0109
  21. Luo JD, Wang YY, Fu WL, Wu J, Chen AF. Gene therapy of endothelial nitric oxide synthase and manganese superoxide dismutase restores delayed wound healing in type 1 diabetic mice. Circulation. 2004;110:2484-2493. https://doi.org/10.1161/01.CIR.0000137969.87365.05
  22. Bradshaw AD, Francki A, Motamed K, Howe C, Sage EH. Primary mesenchymal cells isolated from SPARC-null mice exhibit altered morphology and rates of proliferation. Mol Biol Cell. 1999;10:1569-1579. https://doi.org/10.1091/mbc.10.5.1569
  23. Kim YS, Cho KO, Lee HJ, Kim SY, Sato Y, Cho YJ. Down syndrome candidate region 1 increases the stability of the IkappaBalpha protein: implications for its anti-inflammatory effects. J Biol Chem. 2006;281:39051-39061. https://doi.org/10.1074/jbc.M604659200
  24. Kim YS, Lee HJ, Jang C, Kim HS, Cho YJ. Knockdown of RCAN1.4 increases susceptibility to FAS-mediated and DNAdamage- induced apoptosis by upregulation of p53 expression. Korean J Physiol Pharmacol. 2009;13:483-489. https://doi.org/10.4196/kjpp.2009.13.6.483
  25. Hummel KP, Dickie MM, Coleman DL. Diabetes, a new mutation in the mouse. Science. 1966;153:1127-1128. https://doi.org/10.1126/science.153.3740.1127
  26. Yang J, Rothermel B, Vega RB, Frey N, McKinsey TA, Olson EN, Bassel-Duby R, Williams RS. Independent signals control expression of the calcineurin inhibitory proteins MCIP1 and MCIP2 in striated muscles. Circ Res. 2000;87:E61-68. https://doi.org/10.1161/01.RES.87.12.e61
  27. David KC, Scott RH, Nixon GF. Advanced glycation endproducts induce a proliferative response in vascular smooth muscle cells via altered calcium signaling. Biochem Pharmacol. 2008; 76:1110-1120. https://doi.org/10.1016/j.bcp.2008.08.011
  28. Minami T, Horiuchi K, Miura M, Abid MR, Takabe W, Noguchi N, Kohro T, Ge X, Aburatani H, Hamakubo T, Kodama T, Aird WC. Vascular endothelial growth factor- and thrombin-induced termination factor, Down syndrome critical region-1, attenuates endothelial cell proliferation and angiogenesis. J Biol Chem. 2004;279:50537-50554. https://doi.org/10.1074/jbc.M406454200
  29. Simon M, Rockl W, Hornig C, Grone EF, Theis H, Weich HA, Fuchs E, Yayon A, Grone HJ. Receptors of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) in fetal and adult human kidney: localization and [125I]VEGF binding sites. J Am Soc Nephrol. 1998;9:1032-1044.
  30. Cooper ME, Vranes D, Youssef S, Stacker SA, Cox AJ, Rizkalla B, Casley DJ, Bach LA, Kelly DJ, Gilbert RE. Increased renal expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 in experimental diabetes. Diabetes. 1999;48:2229-2239. https://doi.org/10.2337/diabetes.48.11.2229
  31. Wang P, Heitman J. The cyclophilins. Genome Biol. 2005;6:226. https://doi.org/10.1186/gb-2005-6-7-226
  32. Mehta S, Li H, Hogan PG, Cunningham KW. Domain architecture of the regulators of calcineurin (RCANs) and identification of a divergent RCAN in yeast. Mol Cell Biol. 2009;29:2777-2793. https://doi.org/10.1128/MCB.01197-08
  33. Ke H, Huai Q. Structures of calcineurin and its complexes with immunophilins-immunosuppressants. Biochem Biophys Res Commun. 2003;311:1095-1102. https://doi.org/10.1016/S0006-291X(03)01537-7
  34. Cho YJ, Abe M, Kim SY, Sato Y. Raf-1 is a binding partner of DSCR1. Arch Biochem Biophys. 2005;439:121-128. https://doi.org/10.1016/j.abb.2005.05.002
  35. Lee EJ, Seo SR, Um JW, Park J, Oh Y, Chung KC. NFkappaB- inducing kinase phosphorylates and blocks the degradation of Down syndrome candidate region 1. J Biol Chem. 2008;283:3392-3400. https://doi.org/10.1074/jbc.M706707200
  36. Seo SR, Chung KC. CREB activates proteasomal degradation of DSCR1/RCAN1. FEBS Lett. 2008;582:1889-1893. https://doi.org/10.1016/j.febslet.2008.04.059
  37. Asada S, Ikeda A, Nagao R, Hama H, Sudo T, Fukamizu A, Kasuya Y, Kishi T. Oxidative stress-induced ubiquitination of RCAN1 mediated by SCFbeta-TrCP ubiquitin ligase. Int J Mol Med. 2008;22:95-104.
  38. Lee JY, Lee HJ, Lee EJ, Jang SH, Kim H, Yoon JH, Chung KC. Down syndrome candidate region-1 protein interacts with Tollip and positively modulates interleukin-1 receptor-mediated signaling. Biochim Biophys Acta. 2009;1790:1673-1680. https://doi.org/10.1016/j.bbagen.2009.08.005
  39. Lee HJ, Kim YS, Sato Y, Cho YJ. RCAN1-4 knockdown attenuates cell growth through the inhibition of Ras signaling. FEBS Lett. 2009;583:2557-2564. https://doi.org/10.1016/j.febslet.2009.07.023

Cited by

  1. Regulator of calcineurin 1-4과 파골세포 분화의 관련성 vol.25, pp.2, 2011, https://doi.org/10.5352/jls.2015.25.2.223
  2. RCAN1-4 is a thyroid cancer growth and metastasis suppressor vol.2, pp.5, 2011, https://doi.org/10.1172/jci.insight.90651
  3. Effect of Ultraviolet-C Radiation and Melatonin Stress on Biosynthesis of Antioxidant and Antidiabetic Metabolites Produced in In Vitro Callus Cultures of Lepidium sativum L. vol.20, pp.7, 2011, https://doi.org/10.3390/ijms20071787
  4. RCAN1.4 mediates high glucose-induced matrix production by stimulating mitochondrial fission in mesangial cells vol.40, pp.1, 2011, https://doi.org/10.1042/bsr20192759
  5. Lights triggered differential accumulation of antioxidant and antidiabetic secondary metabolites in callus culture of Eclipta alba L. vol.15, pp.6, 2011, https://doi.org/10.1371/journal.pone.0233963
  6. Increased basal antioxidant levels in RCAN1 - deficient mice lowers oxidative injury after acute paraquat insult vol.54, pp.6, 2011, https://doi.org/10.1080/10715762.2020.1798002
  7. Regulators of calcineurin 1 deficiency attenuates tubulointerstitial fibrosis through improving mitochondrial fitness vol.34, pp.11, 2011, https://doi.org/10.1096/fj.202000781rrr
  8. Regulator of calcineurin 1 gene isoform 4 in pancreatic ductal adenocarcinoma regulates the progression of tumor cells vol.40, pp.17, 2021, https://doi.org/10.1038/s41388-021-01763-z
  9. A Rare Autosomal Dominant Variant in Regulator of Calcineurin Type 1 (RCAN1) Gene Confers Enhanced Calcineurin Activity and May Cause FSGS vol.32, pp.7, 2011, https://doi.org/10.1681/asn.2020081234