Effect of immunosuppression on the human mesangial cell cycle

Zhou,Xiaoshuang; Workeneh,Biruh; Hu,Zhaoyong; Li,Rongshan

doi:10.3892/mmr.2014.2861

Effect of immunosuppression on the human mesangial cell cycle

Authors:
- Xiaoshuang Zhou
- Biruh Workeneh
- Zhaoyong Hu
- Rongshan Li
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Affiliations: Department of Nephrology, Provincial People's Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China, Department of Nephrology, Baylor College of Medicine, Houston, TX 77030, USA
Published online on: November 4, 2014 https://doi.org/10.3892/mmr.2014.2861
Pages: 910-916
Copyright: © Zhou et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

The present study investigated the effects of immunosuppressive agents [tacrolimus (Tac), cyclosporine A (CsA), mycophenolic acid (MMF) and methylprednisone (MP)] on the proliferation, cell cycle progression and apoptotic rate of human mesangial cells. Cultured human mesangial cells were treated with several concentrations of the immunosuppressive agents for 24, 48 or 72 h. Cell cycle progression, proliferation and apoptosis were analyzed using an MTT assay and flow cytometry. Tac and CsA significantly inhibited the proliferation of human mesangial cells in a dose- and time-dependent manner. Cell cycle analysis revealed that Tac and CsA arrested mesangial cells in the G0/G1 phase, preventing them from entering S phase. Similarly, MP inhibited human mesangial cell growth by causing cell cycle arrest in G0/G1 phase. MMF also inhibited mesangial cell proliferation, but accomplished this by preventing progression from S phase to the G2/M phase. The combination of MP and MMF synergistically inhibited mesangial cell proliferation. Tac, CsA, MP and MMF inhibited proliferation of human mesangial cells by blocking progression of the cell cycle. In conclusion, these agents, sequentially or in combination, may be used to effectively treat mesangial proliferative glomerular disease.

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1	Akool el-S, Doller A, Babelova A, Tsalastra W, Moreth K, Schaefer L, Pfeilschifter J and Eberhardt W: Molecular mechanisms of TGF beta receptor-triggered signaling cascades rapidly induced by the calcineurin inhibitors cyclosporin A and FK506. J Immunol. 181:2831–2845. 2008. View Article : Google Scholar
2	Trachtman H, Vento s, Gipson D, et al: Novel therapies for resistant focal segmental glomerulosclerosis (FONT) phase II clinical trial: study design. BMC Nephrol. 12:82011. View Article : Google Scholar : PubMed/NCBI
3	Ponticelli C and Passerini P: Other immunosuppressive agents for focal segmental glomerulosclerosis. Semin Nephrol. 23:242–248. 2003. View Article : Google Scholar : PubMed/NCBI
4	Sabuda-Widemann D, Grabensee B, Schwandt C and Blume C: Mycophenolic acid inhibits the autocrine PDGF-B synthesis and PDGF-BB-induced mRNA expression of Egr-1 in rat mesangial cells. Nephrol Dial Transplant. 24:52–61. 2009. View Article : Google Scholar
5	Radeke HH, Kuster S, Kaever V and Resch K: Effects of cyclosporin and FK-506 on glomerular mesangial cells. Evidence for direct inhibition of thromboxane synthase by low cyclosporin concentrations. Eur J Clin Pharmacol. 44(Suppl 1): S11–S16. 1993. View Article : Google Scholar : PubMed/NCBI
6	Miao L, Sun J, Yuan H, Jia Y and Xu Z: Combined therapy of low-dose tacrolimus and prednisone in nephrotic syndrome with slight mesangial proliferation. Nephrology (Carlton). 11:449–454. 2006. View Article : Google Scholar
7	Pastukhov O, Schwalm S, Römer I, Zangemeister-Wittke U, Pfeilschifter J and Huwiler A: Ceramide kinase contributes to proliferation but not to prostaglandin E2 formation in renal mesangial cells and fibroblasts. Cell Physiol Biochem. 34:119–133. 2014. View Article : Google Scholar : PubMed/NCBI
8	Anil KMS, Irfan SM, Ranganna K, Malat G, Sustento-Reodica N, Kumar AM and Meyers WC: Comparison of four different immunosuppression protocols without long-term steroid therapy in kidney recipients monitored by surveillance biopsy: five-year outcomes. Transpl Immunol. 20:32–42. 2008. View Article : Google Scholar
9	Boletis J, Balitsari A, Filiopoulos V, Stamataki E, Lionaki S, Zavos G and Kostakis A: Delayed renal graft function: the influence of immunosuppression. Transplant Proc. 37:2054–2059. 2005. View Article : Google Scholar : PubMed/NCBI
10	Ren H, Guo N and Lu D: Successful engraftment of HLA-identical sibling cord blood transplantation in an adult with chronic myelogenous leukemia. Chinese Journal of Hematology. 22:621–624. 2001.(In Chinese).
11	Kurogi Y: Mesangial cell proliferation inhibitors for the treatment of proliferative glomerular disease. Med Res Rev. 23:15–31. 2003. View Article : Google Scholar
12	Delarue F, Virone A, Hagege J, Lacave R, Peraldi MN, Adida C, Rondeau E, Feunteun J and Sraer JD: Stable cell line of T-SV40 immortalized human glomerular visceral epithelial cells. Kidney Int. 40:906–912. 1991. View Article : Google Scholar : PubMed/NCBI
13	Ruan XZ, Varghese Z, Fernando R and Moorhead JF: Cytokine regulation of low-density lipoprotein receptor gene transcription in human mesangial cells. Nephrol Dial Transplant. 13:1391–1397. 1998. View Article : Google Scholar : PubMed/NCBI
14	Pereira RL, Felizardo RJ, Cenedeze MA, et al: Balance between the two kinin receptors in the progression of experimental focal and segmental glomerulosclerosis in mice. Dis Mod Mech. 7:701–710. 2014. View Article : Google Scholar
15	Liu CY, Zhou LL, Cheng Q, Jiang SN, Sheng J, Sun JD and Zhao JY: Effect of bradykinin on renal mesangial cell proliferation and extracellular matrix secretion. Genet Mol Res. 13:490–498. 2014. View Article : Google Scholar : PubMed/NCBI
16	Jennings P, Koppelstaetter C, Aydin S, Abberger T, Wolf AM, Mayer G and Pfaller W: Cyclosporine A induces senescence in renal tubular epithelial cells. Am J Physiol Renal Physiol. 293:F831–F838. 2007. View Article : Google Scholar : PubMed/NCBI
17	Choi SJ, You HS and Chung SY: Tacrolimus-induced apoptotic signal transduction pathway. Transplant Proc. 40:2734–2736. 2008. View Article : Google Scholar : PubMed/NCBI
18	Migita K and Eguchi K: FK 506-mediated T-cell apoptosis induction. Transplant Proc. 33:2292–2293. 2001. View Article : Google Scholar : PubMed/NCBI
19	Park JW, Bae EH, Kim IJ, Ma SK, Choi C, Lee J and Kim SW: Paricalcitol attenuates cyclosporine-induced kidney injury in rats. Kidney Int. 77:1076–1085. 2010. View Article : Google Scholar : PubMed/NCBI
20	de Arriba G, de Hornedo JP, Rubio SR, Fernández MC, Martinez SB, Camarero MM and Cid TP: Vitamin E protects against the mitochondrial damage caused by cyclosporin A in LLC-PK1 cells. Toxicol Appl Pharmacol. 239:241–250. 2009. View Article : Google Scholar : PubMed/NCBI
21	Bladh LG, Lidén J, Pazirandeh A, Rafter I, Dahlman-Wright K, Nilsson S and Okret S: Identification of target genes involved in the antiproliferative effect of glucocorticoids reveals a role for nuclear factor-(kappa)B repression. Mol Endocrinol. 19:632–643. 2005. View Article : Google Scholar
22	Rogatsky I, Trowbridge JM and Garabedian MJ: Glucocorticoid receptor-mediated cell cycle arrest is achieved through distinct cell-specific transcriptional regulatory mechanisms. Mol Cell Biol. 17:3181–3193. 1997.PubMed/NCBI
23	Smith E, Redman RA, Logg CR, Coetzee GA, Kasahara N and Frenkel B: Glucocorticoids inhibit developmental stage-specific osteoblast cell cycle. Dissociation of cyclin A-cyclin-dependent kinase 2 from E2F4-p130 complexes. J Biol Chem. 275:19992–20001. 2000. View Article : Google Scholar : PubMed/NCBI
24	Rhee K, Reisman D, Bresnahan W and Thompson EA: Glucocorticoid regulation of G1 cyclin-dependent kinase genes in lymphoid cells. Cell Growth Differ. 6:691–698. 1995.PubMed/NCBI
25	Helmberg A, Auphan N, Caelles C and Karin M: Glucocorticoid-induced apoptosis of human leukemic cells is caused by the repressive function of the glucocorticoid receptor. EMBO J. 14:452–460. 1995.PubMed/NCBI
26	Sánchez I, Goya L, Vallerga AK and Firestone GL: Glucocorticoids reversibly arrest rat hepatoma cell growth by inducing an early G1 block in cell cycle progression. Cell Growth Differ. 4:215–225. 1993.PubMed/NCBI
27	Corroyer S, Nabeyrat E and Clement A: Involvement of the cell cycle inhibitor CIP1/WAF1 in lung alveolar epithelial cell growth arrest induced by glucocorticoids. Endocrinology. 138:3677–3685. 1997.PubMed/NCBI
28	Cha HH, Cram EJ, Wang EC, Huang AJ, Kasler HG and Firestone GL: Glucocorticoids stimulate p21 gene expression by targeting multiple transcriptional elements within a steroid responsive region of the p21waf1/cip1 promoter in rat hepatoma cells. J Biol Chem. 273:1998–2007. 1998. View Article : Google Scholar : PubMed/NCBI