Causes and mechanisms of peritoneal fibrosis and possible application of NF-κB inhibitor for prevention and treatment

Andrzej Bręborowicz; Kazuo Umezawa

doi:10.20883/jms.352

Authors

Andrzej Bręborowicz Department of Pathophysiology, Poznan University of Medical Sciences, Poland https://orcid.org/0000-0002-0916-623X
Kazuo Umezawa Department of Molecular Target Medicine, Aichi Medical University, Nagakute, Japan https://orcid.org/0000-0001-9235-4874

DOI:

https://doi.org/10.20883/jms.352

Keywords:

fibrosis, peritoneal dialysis, NF-κB

Abstract

Peritoneal dialysis is an established form of the renal replacement therapy in patients with end stage renal failure. Continuous Ambulatory Peritoneal Dialysis developed by Moncrief and Popovich in 1975 was a revolutionary event, and contributed much to wide application of that form of treatment in uremic patients. On the other hand, the weak point of peritoneal dialysis is relatively short viability of the peritoneum as the dialysis membrane. Two main peritoneal pathologies are observed in patients treated with that form of renal replacement therapy: neovascularization of the membrane what causes increased peritoneal permeability to osmotic solutes and ultrafiltration failure, and fibrosis which results also in ultrafiltration failure due to its decreased hydraulic conductivity and reduced permeability to uremic toxins. Meanwhile, an NF-κB inhibitor DHMEQ was discovered in 2000 and has been successfully used to suppress various inflammatory and neoplastic disease models. NF-κB is likely to be involved in the mechanism of peritoneal inflammation and fibrosis. We have studied whether DHMEQ would inhibit cellular model of peritoneal inflammation and fibrosis. It inhibited inflammatory cytokine and collagen productions in primary culture of human peritoneal mesothelial cells, and intraperitoneal administration of NF-κB inhibitors would be useful to suppress peritoneal fibrosis.

Downloads

Download data is not yet available.

References

Popovich RP, Moncrief JW, Decherd JF, Bomar JB, Pyle WK. The definition of a novel portable/wearable equilibrium dialysis technique (abstract). Trans Am Soc Artif Intern Organs. 1976;5:64.

Struijk DG. Peritoneal Dialysis in Western Countries. Kidney Dis (Basel). 2015; 1:157–164.

Krediet RT. Preservation of Residual Kidney Function and Urine Volume in Patients on Dialysis. Clin J Am Soc Nephrol. 2017;12:377–379.

Jain D, Haddad DB, Goel N. Choice of dialysis modality prior to kidney transplantation: Does it matter? World J Nephrol. 2019;8:1–10.

Jain AK, Blake P, Cordy P, Garg AX. Global trends in rates of peritoneal dialysis. J Am Soc Nephrol. 2012;23:533–544.

Davies SJ, Bryan J, Phillips L, Russell GI. Longitudinal changes in peritoneal kinetics: the effects of peritoneal dialysis and peritonitis. Nephrol Dial Transplant. 1996;11:498–506.

de Lima SM, Otoni A, Sabino AP, Dusse LM, Gomes KB, Pinto SW, et al. Inflammation, neoangiogenesis and fibrosis in peritoneal dialysis. Clin Chim Acta. 2013;421:46–50.

Danford CJ, Lin SC, Smith MP, Wolf J, Encapsulating peritoneal sclerosis. World J Gastroenterol. 2018;24:3101–3111.

Brown EA, Bargman J, van Biesen W, Chang MY, Finkelstein FO, Hurst H, Johnson DW, et al. Length of Time on Peritoneal Dialysis and Encapsulating Peritoneal Sclerosis — Position Paper for ISPD: 2017 Update. Perit Dial Int. 2017;37:362–374.

Honda K, Hamada C, Nakayama M, Miyazaki M, Sherif AM, Harada T, et al. Peritoneal Biopsy Study Group of the Japanese Society for Peritoneal Dialysis. Impact of uremia, diabetes, and peritoneal dialysis itself on the pathogenesis of peritoneal sclerosis: a quantitative study of peritoneal membrane morphology. Clin J Am Soc Nephrol. 2008;3:720–728.

van Esch S, van Diepen ATN, Struijk DG, Krediet RT. The mutual relationship between peritonitis and peritoneal transport. Perit Dial Int. 2016;36:33–42.

Di Paolo N, Sacchi G. Atlas of peritoneal histology — in normal conditions and during peritoneal dialysis. Perit Dial Int. 2000;20:S5–S10.

Flessner MF, Credit K, Henderson K. Peritoneal changes after exposure to sterile solutions by catheter. J Am Soc Nephrol. 2007;18:2294–302.

Breborowicz A, Rodela H, Karoń J, Martis L, Oreopoulos DG. In vitro simulation of the effect of peritoneal dialysis solution on mesothelial cells. Am J Kidney Dis. 1997;29:404–409.

Wieczorowska‑Tobis K, Polubinska A, Schaub TP, Schilling H, Wisniewska J, Witowski J, et al. Influence of neutral‑pH dialysis solutions on the peritoneal membrane: a long‑term investigation in rats. Perit Dial Int. 2001;21(Suppl 3):S108-S113.

Breborowicz A, Rodela H, Oreopoulos DG. Toxicity of osmotic solutes on human mesothelial cells in vitro. Kidney Int. 1992;41:1280–1285.

Ksiazek K, Breborowicz A, Jörres A, Witowski J. Oxidative stress contributes to accelerated development of the senescent phenotype in human peritoneal mesothelial cells exposed to high glucose. Free Radic Biol Med. 2007;42:636–641.

Zhang X, Liang D, Guo B, Yang L, Wang L, Ma J. Zinc inhi-

bits high glucose‑induced apoptosis in peritoneal meso-

thelial cells. Biol Trace Elem Res. 2012;150:424–432.

López‑Cabrera M. Mesenchymal Conversion of Mesothelial Cells Is a Key Event in the Pathophysiology of the Peritoneum during Peritoneal Dialysis. Adv Med. 2014;2014:473134.

Strippoli R, Moreno‑Vicente R, Battistelli C, Cicchini C, Noce V, Amicone L, et al. Molecular Mechanisms Underlying Peritoneal EMT and Fibrosis. Stem Cells Int. 2016;3543678.

Lopez‑Anton M, Rudolf A, Baird DM, Roger L, Jones RE, Witowski J, et al. Telomere length profiles in primary human peritoneal mesothelial cells are consistent with senescence. Mech Ageing Dev. 2017;164:37–40.

Yu MA, Shin KS, Kim JH, Kim YI, Chung SS, Park SH, et al. HGF and BMP-7 ameliorate high glucose‑induced epithelial‑to‑mesenchymal transition of peritoneal mesothelium. J Am Soc Nephrol. 2009;20:567–581.

Ogunwobi OO, Liu C, Hepatocyte growth factor upregulation promotes carcinogenesis and epithelial‑mesenchymal transition in hepatocellular carcinoma via Akt and COX-2 pathways. Clin Exp Metastasis. 2011;28:721–731.

Strippoli R, Benedicto I, Foronda M, Perez‑Lozano ML, Sánchez‑Perales S, López‑Cabrera M, et al. p38 maintains E‑cadherin expression by modulating TAK1-NF‑kappa B during epithelial‑to‑mesenchymal transition. J Cell Sci. 2010;123:4321–4331.

Kokoroishi K, Nakashima A, Doi S, Ueno T, Doi T, Yokoyama Y, et al. High glucose promotes TGF‑β1 production by inducing FOS expression in human peritoneal mesothelial cells. Clin Exp Nephrol. 2016;20:30–38.

Patel P, Sekiguchi Y, Oh KH, Patterson SE, Kolb MR, Margetts PJ. Smad3-dependent and -independent pathways are involved in peritoneal membrane injury. Kidney Int. 2010;77:319–328.

Loureiro J, Schilte M, Aguilera A, Albar‑Vizcaíno P, Ramírez‑Huesca M, Pérez‑Lozano ML, et al. BMP-7 blocks mesenchymal conversion of mesothelial cells and prevents peritoneal damage induced by dialysis fluid exposure. Nephrol Dial Transplant. 2010;25:1098–1108.

Strippoli R, Benedicto I, Perez Lozano ML, Pellinen T, Sandoval P, Lopez‑Cabrera M, et al. Inhibition of transforming growth factor‑activated kinase 1 (TAK1) blocks and reverses epithelial to mesenchymal transition of mesothelial cells. PLoS One. 2012;7:e31492.

Strippoli R, Benedicto I, Pérez Lozano ML, Cerezo A, López‑Cabrera M, del Pozo MA. Epithelial‑to‑mesenchymal transition of peritoneal mesothelial cells is regulated by an ERK/NF‑kappaB/Snail1 pathway. Dis Model Mech. 2008;1:264–274.

Farhat K, Douma CE, Ferrantelli E, Ter Wee PM, Beelen RHJ, van Ittersum FJ. Effects of Conversion to a Bicarbonate/Lactate‑Buffered, Neutral‑pH, Low‑GDP PD Regimen in Prevalent PD: A 2-Year Randomized Clinical Trial. Perit Dial Int. 2017;37:273–282.

Yung S, Lui SL, Ng CK, Yim A, Ma MK, Lo KY, et al. Impact of a low‑glucose peritoneal dialysis regimen on fibrosis and inflammation biomarkers. Perit Dial Int. 2015;35:147–158.

Aoki S, Noguchi M, Takezawa T, Ikeda S, Uchihashi K, Kuroyama H, et al. Fluid dwell impact induces peritoneal fibrosis in the peritoneal cavity reconstructed in vitro. J Artif Organs. 2016;19:87–96.

Morinelli TA, Luttrell LM, Strungs EG, Ullian ME. Angiotensin II receptors and peritoneal dialysis‑induced peritoneal fibrosis. Int J Biochem Cell Biol. 2016;77(Pt B):240–50.

Kyuden Y, Ito T, Masaki T, Yorioka N, Kohno N. TGF‑beta1 induced by high glucose is controlled by angiotensin‑converting enzyme inhibitor and angiotensin II receptor blocker on cultured human peritoneal mesothelial cells. Perit Dial Int. 2005;25:483–491.

Nagami GT, Chang JA, Plato ME, Santamaria R. Acid loading in vivo and low pH in culture increase angiotensin receptor expression: enhanced ammoniagenic response to angiotensin II. Am J Physiol Renal Physiol. 2008;295:F1864–F1870.

Duman S, Sen S, Duman C, Oreopoulos DG. Effect of valsartan versus lisinopril on peritoneal sclerosis in rats. Int J Artif Organs. 2005;28:156–163.

Yang L, Fan Y, Zhang X, Huang W, Ma J. 1,25(OH)2D3 treatment attenuates high glucose‑induced peritoneal epithelial to mesenchymal transition in mice. Mol Med Rep. 2017;16:3817–3824.

Wu J, Xing C, Zhang L, Mao H, Chen X, Liang M, et al. Autophagy promotes fibrosis and apoptosis in the peritoneum during long‑term peritoneal dialysis. J Cell Mol Med. 2018;22:1190–1201.

Lupinacci S, Perri A, Toteda G, Vizza D, Puoci F, Parisi OI, et al. Olive leaf extract counteracts epithelial to mesenchymal transition process induced by peritoneal dialysis, through the inhibition of TGFβ1 signaling. Cell Biol Toxicol. 2018. doi: 10.1007/s10565-018-9438-9.

Cheng S, Lu Y, Li Y, Gao L, Shen H, Song K. Hydrogen sulfide inhibits epithelial‑mesenchymal transition in peritoneal mesothelial cells. Sci Rep. 2018;8:5863. doi: 10.1038/s41598-018-21807-x.

Masola V, Granata S, Bellin G, Gambaro G, Onisto M, Rugiu C, et al. Specific heparanase inhibition reverses glucose‑induced mesothelial‑to‑mesenchymal transition. Nephrol Dial Transplant. 2017;32:1145–1154.

Wakabayashi K, Hamada C, Kanda R, Nakano T, Io H, Horikoshi S, et al. Oral Astaxanthin supplementation prevents peritoneal fibrosis in rats. Perit Dial Int. 2015;35:506–516.

Liu J, Zeng L, Zhao Y, Zhu B, Ren W, Wu C. Selenium suppresses lipopolysaccharide‑induced fibrosis in peritoneal mesothelial cells through inhibition of epithelial‑to‑mesenchymal transition. Biol Trace Elem Res. 2014;161:202–209.

Su X, Zhou G, Wang Y, Yang X, Li L, Yu R, et al. The PPARβ/δ agonist GW501516 attenuates peritonitis in peritoneal fibrosis via inhibition of TAK1-NFκB pathway in rats. Inflammation. 2014;37:729–737.

Kitamura M, Nishino T, Obata Y, Furusu A, Hishikawa Y, Koji T, et al. Epigallocatechin gallate suppresses peritoneal fibrosis in mice. Chem Biol Interact. 2012;195:95–104.

Washida N, Wakino S, Tonozuka Y, Homma K, Tokuyama H, Hara Y et al. Rho‑kinase inhibition ameliorates peritoneal fibrosis and angiogenesis in a rat model of peritoneal sclerosis. Nephrol Dial Transplant. 2011;26:2770–2779.

Erkel G, Anke T, Sterner O. Inhibition of NF‑κB activation by panepoxydone. Biochem Biophys Res Commun. 1996;226:214–221.

Gehrt A, Erkel G, Anke T, Sterner OA. Cycloepoxydon: 1-hydroxy-2-hydroxymethyl-3-pent-1-enylbenzene1-hydroxy-2-hydroxymethyl-3-pent-1, 3-dienylbenzene, new inhibitors of eukaryotic signal transduction. J Antibiot. 1998;51:455–463.

Matsumoto N, Ariga A, Toe S, Nakamura H, Agata N, Hirano S, et al. Synthesis of NF‑κB activation inhibitors derived from epoxyquinomicin C. Bioorg Med Chem Lett. 2000;10:865–869.

Suzuki Y, Sugiyama C, Ohno O, Umezawa K. Preparation and biological activities of optically active dehydroxymethylepoxyquinomicin, a novel NF‑κB inhibitor. Tetrahedron. 2004;60:7061–7066.

Hamada M, Niitsu Y, Hiraoka C, Kozawa I, Higashi T, Shoji M. et al. Chemoenzymatic synthesis of (2S,3S,4S)-form, the physiologically active stereoisomer of dehydroxymethylepoxyquinomicin (DHMEQ), a potent inhibitor on NF‑κB. Tetrahedron. 2010;66:7083–7087.

Ariga A, Namekawa J, Matsumoto N, Inoue J, Umezawa K. Inhibition of TNF‑α-induced nuclear translocation and activation of NF‑κB by dehydroxymethyl‑epoxyquinomicin. J Biol Chem. 2002;277:27625–27630.

Yamamoto M, Horie R, Takeiri M, Kozawa I, Umezawa K. Inactivation of nuclear factor kappa B components by covalent binding of (−)-dehydroxymethylepoxyquinomicin to specific cysteine residues. J Med Chem. 2008;51:5780–5788.

Horie K, Ma J, Umezawa K. Inhibition of canonical NF‑κB nuclear localization by (−)-DHMEQ via impairment of DNA binding. Oncology Res. 2015;22:105–115.

Kozawa I, Kato K, Teruya T, Suenaga K, Umezawa K. Unusual intramolecular N→O acyl group migration occurring during conjugation of (−)-DHMEQ with cysteine. Bioorg Med Chem Lett. 2009;19:5380–5382.

Shimada C, Ninomiya Y, Suzuki E, Umezawa K. Efficient cellular uptake of the novel NF‑κB inhibitor (−)-DHMEQ and irreversible inhibition of NF‑κB in neoplastic cells. Oncology Research. 2010;18:529–535.

Takeiri M, Horie K, Takahashi D, Watanabe M, Horie R, Simizu S, et al. Involvement of DNA binding domain in the cellular stability and importin affinity of NF‑κB component RelB. Org Biomol Chem. 2012;10:3053–3059.

Takatsuna, H, Asagiri M, Kubota T, Oka K, Osada T, Sugiyama C, et al. Inhibition of RANKL‑induced osteoclastogenesis by (-)-DHMEQ, a novel NF‑κB inhibitor, through downregulation of NFATc1. J. Bone Mineral Res. 2005;20:653–661.

Kubota T, Hoshino M, Aoki K, Ohya K, Komano Y, Nanki T, et al. NF‑κB inhibitor DHMEQ suppresses osteoclastogenesis and expression of NFATc1 in mouse arthritis without affecting expression of RANCL, OPG or M‑CSF. Arthritis Research & Therapy. http://arthritis‑research.com/content/9/5//R97, 2007.

Murohashi M, Hinohara K, Kuroda M, Isagawa T, Tsuji S, Kobayashi S, et al. Gene set enrichment analysis provides insight into novel signaling pathways in breast cancer stem cells. British J Cancer. 2010;102:206–212.

Hinohara K, Kobayashi S, Simizu S, Tada K, Tsuji E, Nishioka K, et al. ErbB receptor tyrosine kinase/NF‑κB signaling controls mammosphere formation in human breast cancer. Proc Natl Acad Sci USA. 2012;109:6584–6589.

Ukaji T, Lin Y, Okada S, Umezawa K. Inhibition of MMP-2-mediated cellular invasion by NF‑κB inhibitor DHMEQ in 3D culture of breast carcinoma MDA‑MB-231 cells: A model for early phase of metastasis. Biochem Biophys Res Commun. 2017;485:76–81.

Suzuki K, Aiura K, Matsuda S, Itano O, Takeuchi O, Umezawa K, et al. Combined effect of dehydroxymethylepoxyquinomicin and gemcitabine in a mouse model of liver metastasis of pancreatic cancer. Clinical & Experimental Metastasis. 2013;30:381–392.

Lin Y, Ukaji T, Koide N, Umezawa K. Inhibition of late and early phases of cancer metastasis by NF‑κB inhibitor DHMEQ derived from microbial bioactive metabolite epoxyquinomicin: A review. Int J Mol Sci. 2018;19:729. doi: 10.3390/ijms19030729.

Hamasaka A, Yoshioka N, Abe R, Kishino S, Umezawa K, Ozaki M, et al. Topical application of DHMEQ improves allergic inflammation via NF‑κB inhibition. Journal of Allergy and Clinical Immunology. 2010;126:400–403.

Noma N, Asagiri M, Takeiri M, Ohmae S, Takemoto K, Iwaisako K, et al. Inhibition of MMP-2-mediated mast cell invasion by NF‑κB inhibitor DHMEQ in mast cells. International Achieves of Allergy and Immunology. 2015;166:84–90.

Jiang X, Wei B, Lan Y, Dai C, Gu Y, Ma J, et al. External application of NF‑κB inhibitor DHMEQ suppresses development of atopic dermatitis‑like lesions induced with DNCB/OX in BALB/c mice. Immunopharmacology and Immunotoxicology. 2017;39:157–164.

Jiang X, He H, Xie Z, Wen H, Li X, Ma J, et al. Dehydroxymethylepoxyquinomicin suppresses atopic dermatitis‑like lesions in a stratum corneum‑removed murine model through NF‑κB inhibition. Immunopharmacology and Immunotoxicology. doi: 10.1080/08923973.2018.1510962.

Kobayashi K, Umezawa K, Yasui M. Apoptosis in mouse amniotic epithelium is induced by activated macrophages through the TNF receptor type 1/TNF pathway. Biology of Reproduction. 2011;84:248–254.

El‑Salhy M, Umezawa K. Effects of AP-1 and NF‑kappa B inhibitors on colonic endocrine cells in rats with TNBS‑induced colitis. Molecular Medicine Reports. 2016;14:1515–1522.

El‑Salhy M, Umezawa K. Anti‑inflammatory effects of novel AP-1 and NF‑κB inhibitors in dextran‑sulfate‑sodium‑induced colitis in rats. International J Mol Med. 2016;37:1457–1464. doi: 10.3892/ijmm.

Kikuchi, E, Horiguchi Y, Nakashima J, Kuroda K, Oya M, Ohigashi T, et al. Suppression of hormone‑refractory prostate cancer by a novel nuclear factor κB inhibitor in nude mice. Cancer Res. 2003;63:107–110.

Matsumoto G, Namekawa J, Muta M, Nakamura T, Bando H, Tohyama K, et al. Targeting of NF‑κB pathways by DHMEQ, a novel inhibitor of breast carcinomas: Anti‑tumor and anti‑angiogenic activity in vivo. Clin Cancer Res. 2005;11:1287–1293.

Starenki DV, Namba H, Saenko VA, Ohtsuru A, Maeda S, Umezawa K, et al. Induction of thyroid cancer cell apoptosis by a novel nuclear factor kappaB inhibitor, DHMEQ. Clin. Cancer Res. 2004;10:6821–6829.

Fukushima T, Kawaguchi M, Yorita K, Tanaka H, Umezawa K, Kataoka H. Antitumor effect of dehydroxymethylepoxyquinomicin (DHMEQ), a small molecule inhibitor of nuclear factor‑κB, on glioblastoma. Neuro‑Oncology. 2012;14:19–28.

Watanabe M, Ohsugi T, Shoda M, Ishida T, Aizawa S, Maruyama‑Nagai M, et al. Dual targeting of transformed and untransformed HTLV-1-infected T‑cells by DHMEQ, a potent and selective inhibitor of NF‑κB, as a strategy for chemoprevention and therapy of adult T cell leukemia. Blood. 2005;106:2462–2471.

Tatetsu H, Okuno Y, Nakamura M, Matsuno F, Sonoki T, Taniguchi I, et al. A novel nuclear factor‑kappa B inhibitor induced apoptosis of multiple myeloma cells. Mol. Cancer Ther. 2005;4:1114–1120.

Seubwai W, Kraiklang R, Vaeteewoottacharn K, Umezawa K, Okada S, Wongkham S. Aberrant expression of NF‑κB in liver fluke associated cholangiocarcinoma: implications for targeted therapy. PLOS ONE. 2014;9 (8), e106056. DOI:10.1371/journal.pone.0106056.

Ito Y, Kikuchi E, Tanaka N, Kosaki T, Suzuki E, Mizuno R, et al. Down‑regulation of NF‑kappa B activation is an effective therapeutic modality in acquired platinum‑resistant bladder cancer. BMC Cancer. 2015;15:324. doi: 10.1186/s12885-015-1315-9.

Umezawa K. Possible role of peritoneal NF‑κB in peripheral inflammation and cancer: Lessons from the inhibitor DHMEQ. Biomedicine & Pharmacotherapy. 2011;65:252–259.

Umezawa K. Peritoneal NF‑κB as a Possible molecular target for suppression of various cancers and inflammation. (Review) Forum of Immunopathological Diseases and Therapeutics. 2013;4:63–77.

Sosinska P, Mackowiak B, Staniszewski R, Umezawa K, Breborowicz A. Inhibition of NF‑κB with dehydroxyepoxiquinomicin modifies function of human peritoneal mesothelial cells. American Journal of Translational Research. 2016;8:5756–5765.