The Korean journal of internal medicine

The Korean Association of Internal Medicine (대한내과학회)
권호 표지
DOI QR코드

DOI QR Code

Effects of colchicine on renal fibrosis and apoptosis in obstructed kidneys

  • Kim, Sejoong (Department of Internal Medicine, Seoul National University College of Medicine) ;
  • Jung, Eun Sook (Department of Internal Medicine, Seoul National University College of Medicine) ;
  • Lee, Jeonghwan (Department of Internal Medicine, Hallym University Hangang Sacred Heart Hospital) ;
  • Heo, Nam Ju (Department of Internal Medicine, Seoul National University College of Medicine) ;
  • Na, Ki Young (Department of Internal Medicine, Seoul National University College of Medicine) ;
  • Han, Jin Suk (Department of Internal Medicine, Seoul National University College of Medicine)
  • Received : 2016.04.18
  • Accepted : 2016.07.16
  • Published : 2018.05.01
⟨ Previous Next ⟩

Abstract

Background/Aims: Colchicine is an established drug for microtubule stabilization that may reduce tissue injury. No data were available that its effects may depend on the dosage of colchicine. We investigated the anti-fibrotic and apoptotic effects of various dose of colchicine in a unilateral ureteral obstruction (UUO) model. Methods: Thirty-six Sprague-Dawley rats were randomly assigned into six groups. Two sham groups were divided into a vehicle-treated or colchicine-treated group ($100{\mu}g/kg/day$). Four UUO groups were treated with either vehicle or three different doses of colchicine for 7 days (30, 60, and $100{\mu}g/kg/day$, intraperitoneally). All of the animals were sacrificed on day 7. Results: Colchicine treatment diminished acetylated ${\alpha}$-tubulin and tumor growth $factor-{\beta}$ immunoreactivities in the cortical area of the 7-day obstructed kidneys, which was in dose dependent manner. Colchicine attenuated tubulointerstitial damage and apoptosis in both cortical and medullary area, and beneficial effects of colchicine therapy were dramatically shown at the higher dosage of colchicine. The expression levels of cleaved caspase-3, ED-1, and fibronectin were decreased in UUO animals. Conclusions: We found that the proper dosage of colchicine may have anti-fibrotic and anti-apoptotic effects in obstructed kidneys. For clinical applications, an optimal dose of colchicine should be evaluated to maximize the prevention of renal disease progression.

Keywords

Acknowledgement

Supported by : National Research Foundation of Korea, Korea Health Industry Development Institute (KHIDI)

References

  1. Kim SK, Cho SM, Kim H, et al. The colchicine derivative CT20126 shows a novel microtubule-modulating activity with apoptosis. Exp Mol Med 2013;45:e19. https://doi.org/10.1038/emm.2013.38
  2. Mollinedo F. Survival and apoptotic signals in the action of microtubule-targeting antitumor drugs. IDrugs 2005;8:127-143.
  3. McClurkin C Jr, Phan SH, Hsu CH, et al. Moderate protection of renal function and reduction of fibrosis by colchicine in a model of anti-GBM disease in the rabbit. J Am Soc Nephrol 1990;1:257-265.
  4. Li C, Yang CW, Ahn HJ, et al. Colchicine decreases apoptotic cell death in chronic cyclosporine nephrotoxicity. J Lab Clin Med 2002;139:364-371. https://doi.org/10.1067/mlc.2002.124397
  5. Li JJ, Lee SH, Kim DK, et al. Colchicine attenuates inflammatory cell infiltration and extracellular matrix accumulation in diabetic nephropathy. Am J Physiol Renal Physiol 2009;297:F200-F209. https://doi.org/10.1152/ajprenal.90649.2008
  6. Guan T, Gao B, Chen G, et al. Colchicine attenuates renal injury in a model of hypertensive chronic kidney disease. Am J Physiol Renal Physiol 2013;305:F1466-F1476. https://doi.org/10.1152/ajprenal.00057.2013
  7. Wilson DR. Nephron functional heterogeneity in the postobstructive kidney. Kidney Int 1975;7:19-26. https://doi.org/10.1038/ki.1975.3
  8. Mason J, Welsch J, Takabatake T. Disparity between surface and deep nephron function early after renal ischemia. Kidney Int 1983;24:27-36. https://doi.org/10.1038/ki.1983.122
  9. Gobe GC, Axelsen RA. Genesis of renal tubular atrophy in experimental hydronephrosis in the rat. Role of apoptosis. Lab Invest 1987;56:273-281.
  10. Truong LD, Choi YJ, Tsao CC, et al. Renal cell apoptosis in chronic obstructive uropathy: the roles of caspases. Kidney Int 2001;60:924-934. https://doi.org/10.1046/j.1523-1755.2001.060003924.x
  11. Yutao X, Geru W, Xiaojun B, Tao G, Aiqun M. Mechanical stretch-induced hypertrophy of neonatal rat ventricular myocytes is mediated by beta(1)-integrin-microtubule signaling pathways. Eur J Heart Fail 2006;8:16-22. https://doi.org/10.1016/j.ejheart.2005.05.014
  12. Kim S, Heo NJ, Jung JY, et al. Changes in the sodium and potassium transporters in the course of chronic renal failure. Nephron Physiol 2010;115:p31-p41. https://doi.org/10.1159/000314542
  13. Na KY, Kim GH, Joo KW, et al. Chronic furosemide or hydrochlorothiazide administration increases H+-ATPase B1 subunit abundance in rat kidney. Am J Physiol Renal Physiol 2007;292:F1701-F1709. https://doi.org/10.1152/ajprenal.00270.2006
  14. Gourlay CW, Ayscough KR. The actin cytoskeleton: a key regulator of apoptosis and ageing? Nat Rev Mol Cell Biol 2005;6:583-589.
  15. Jung HI, Shin I, Park YM, Kang KW, Ha KS. Colchicine activates actin polymerization by microtubule depolymerization. Mol Cells 1997;7:431-437.
  16. Disel U, Paydas S, Dogan A, Gulfiliz G, Yavuz S. Effect of colchicine on cyclosporine nephrotoxicity, reduction of TGF-beta overexpression, apoptosis, and oxidative damage: an experimental animal study. Transplant Proc 2004;36:1372-1376. https://doi.org/10.1016/j.transproceed.2004.05.078
  17. El-Sakka AI, Bakircioglu ME, Bhatnagar RS, Yen TS, Dahiya R, Lue TF. The effects of colchicine on a Peyronie's-like condition in an animal model. J Urol 1999;161:1980-1983. https://doi.org/10.1016/S0022-5347(05)68868-4
  18. Shan B, Yao TP, Nguyen HT, et al. Requirement of HDAC6 for transforming growth factor-beta1-induced epithelial-mesenchymal transition. J Biol Chem 2008;283:21065-21073. https://doi.org/10.1074/jbc.M802786200
  19. Serrador JM, Cabrero JR, Sancho D, Mittelbrunn M, Urzainqui A, Sanchez-Madrid F. HDAC6 deacetylase activity links the tubulin cytoskeleton with immune synapse organization. Immunity 2004;20:417-428. https://doi.org/10.1016/S1074-7613(04)00078-0
  20. Ruwhof C, van der Laarse A. Mechanical stress-induced cardiac hypertrophy: mechanisms and signal transduction pathways. Cardiovasc Res 2000;47:23-37. https://doi.org/10.1016/S0008-6363(00)00076-6
  21. Stone AA, Chambers TC. Microtubule inhibitors elicit differential effects on MAP kinase (JNK, ERK, and p38) signaling pathways in human KB-3 carcinoma cells. Exp Cell Res 2000;254:110-119. https://doi.org/10.1006/excr.1999.4731
  22. Masaki T, Foti R, Hill PA, Ikezumi Y, Atkins RC, Nikolic-Paterson DJ. Activation of the ERK pathway precedes tubular proliferation in the obstructed rat kidney. Kidney Int 2003;63:1256-1264. https://doi.org/10.1046/j.1523-1755.2003.00874.x
  23. Tao Y, Kim J, Faubel S, et al. Caspase inhibition reduces tubular apoptosis and proliferation and slows disease progression in polycystic kidney disease. Proc Natl Acad Sci U S A 2005;102:6954-6959. https://doi.org/10.1073/pnas.0408518102
  24. Zhou B, Rabinovitch M. Microtubule involvement in translational regulation of fibronectin expression by light chain 3 of microtubule-associated protein 1 in vascular smooth muscle cells. Circ Res 1998;83:481-489. https://doi.org/10.1161/01.RES.83.5.481
  25. Park SH, Choi MJ, Song IK, et al. Erythropoietin decreases renal fibrosis in mice with ureteral obstruction: role of inhibiting TGF-beta-induced epithelial-to-mesenchymal transition. J Am Soc Nephrol 2007;18:1497-1507. https://doi.org/10.1681/ASN.2005080866
  26. Chevalier RL, Forbes MS, Thornhill BA. Ureteral obstruction as a model of renal interstitial fibrosis and obstructive nephropathy. Kidney Int 2009;75:1145-1152. https://doi.org/10.1038/ki.2009.86
  27. Kwon TH, Frokiaer J, Nielsen S. Regulation of aquaporin-2 in the kidney: a molecular mechanism of body-water homeostasis. Kidney Res Clin Pract 2013;32:96-102. https://doi.org/10.1016/j.krcp.2013.07.005
  28. Kang SH, Kim J, Park JW. Biopsy-proven type 1 renal tubular acidosis in a patient with metabolic acidosis. Korean J Intern Med 2012;27:119. https://doi.org/10.3904/kjim.2012.27.1.119

Cited by

  1. Unilateral Ureteral Obstruction as a Model to Investigate Fibrosis-Attenuating Treatments vol.9, pp.4, 2018, https://doi.org/10.3390/biom9040141
  2. Colchicine: An Impressive Effect on Posttransplant Capillary Leak Syndrome and Renal Failure vol.143, pp.5, 2018, https://doi.org/10.1542/peds.2018-2820
  3. Benefits and adverse effects of hydroxychloroquine, methotrexate and colchicine: searching for repurposable drug candidates vol.40, pp.11, 2018, https://doi.org/10.1007/s00296-020-04694-2
  4. Analysis of apoptosis of kidney tissue by the tunel method and histomorphological changes in rabbit kidney model due to unilateral supravesical obstruction vol.4, pp.11, 2020, https://doi.org/10.28982/josam.811241
  5. Repurposing of metformin and colchicine reveals differential modulation of acute and chronic kidney injury vol.10, pp.1, 2018, https://doi.org/10.1038/s41598-020-78936-5
  6. Fabry disease exacerbates renal interstitial fibrosis after unilateral ureteral obstruction via impaired autophagy and enhanced apoptosis vol.40, pp.2, 2018, https://doi.org/10.23876/j.krcp.20.264
  7. Cytoskeleton Reorganization in EndMT-The Role in Cancer and Fibrotic Diseases vol.22, pp.21, 2021, https://doi.org/10.3390/ijms222111607