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Shinkai Y, Sasaki K, Tamura R, Ike T, Takahashi A, Osaki Y, Ishiuchi N, Maeoka Y, Nakashima A, Masaki T. Selective activation of PPARα by pemafibrate mitigates peritoneal inflammation and fibrosis through suppression of NLRP3 inflammasome and modulation of inflammation. Sci Rep 2024; 14:23816. [PMID: 39394435 PMCID: PMC11470028 DOI: 10.1038/s41598-024-74340-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Accepted: 09/25/2024] [Indexed: 10/13/2024] Open
Abstract
Peritoneal inflammation and fibrosis remain major challenges to the long-term maintenance of peritoneal dialysis. Pemafibrate, a selective peroxisome proliferator-activated receptor α (PPARα) modulator, has been implicated in the management of fibrosis-related disorders. We investigated whether pemafibrate ameliorates peritoneal inflammation and fibrosis and explored the underlying mechanisms in mice with methylglyoxal (MGO)-induced peritoneal fibrosis (MGO mice). MGO mice exhibited peritoneal fibrosis with increased expression of mesenchymal markers, transforming growth factor-β1 (TGF-β1), and substantial deposition of extracellular matrix (ECM) proteins. Additionally, MGO mice exhibited peritoneal inflammation as indicated by elevated tumor necrosis factor-α expression and macrophage infiltration in peritoneal tissue. These effects were mitigated by pemafibrate treatment, which also restored peritoneal membrane function. Furthermore, pemafibrate promoted anti-inflammatory macrophage polarization in both mice and THP-1 cells. In human peritoneal mesothelial cells (HPMCs), pemafibrate effectively inhibited interferon-γ-induced production of TGF-β1 and ECM while suppressing the proinflammatory cytokines nuclear factor-κB (NF-κB) and activator protein 1. The NF-κB inhibitory effect of pemafibrate involved stabilization of the NF-κB inhibitory protein IkBα. Notably, pemafibrate hindered activation of the NLR family pyrin domain containing 3/caspase-1 axis in interferon-γ-stimulated THP-1 cells. These findings suggest that pemafibrate ameliorates peritoneal inflammation and fibrosis, making it a promising candidate for peritoneal fibrosis therapy.
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Affiliation(s)
- Yutaka Shinkai
- Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Kensuke Sasaki
- Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
| | - Ryo Tamura
- Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Takeshi Ike
- Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Akira Takahashi
- Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Yosuke Osaki
- Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Naoki Ishiuchi
- Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Yujiro Maeoka
- Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Ayumu Nakashima
- Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Takao Masaki
- Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
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Li J, Liu Y, Liu J. A review of research progress on mechanisms of peritoneal fibrosis related to peritoneal dialysis. Front Physiol 2023; 14:1220450. [PMID: 37817984 PMCID: PMC10560738 DOI: 10.3389/fphys.2023.1220450] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Accepted: 09/13/2023] [Indexed: 10/12/2023] Open
Abstract
Peritoneal dialysis (PD) is an effective alternative treatment for patients with end-stage renal disease (ESRD) and is increasingly being adopted and promoted worldwide. However, as the duration of peritoneal dialysis extends, it can expose problems with dialysis inadequacy and ultrafiltration failure. The exact mechanism and aetiology of ultrafiltration failure have been of great concern, with triggers such as biological incompatibility of peritoneal dialysis solutions, uraemia toxins, and recurrent intraperitoneal inflammation initiating multiple pathways that regulate the release of various cytokines, promote the transcription of fibrosis-related genes, and deposit extracellular matrix. As a result, peritoneal fibrosis occurs. Exploring the pathogenic factors and molecular mechanisms can help us prevent peritoneal fibrosis and prolong the duration of Peritoneal dialysis.
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Affiliation(s)
- Jin’e Li
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Yinghong Liu
- Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, China
| | - Jianping Liu
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, China
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Lin CE, Lin PY, Yang WC, Huang YS, Lin TY, Chen CM, Chen HS, Lee JA, Chen SM. Evaluation of the nephrotoxicity and safety of low-dose aristolochic acid, extending to the use of Xixin (Asurum), by determination of methylglyoxal and d-lactate. JOURNAL OF ETHNOPHARMACOLOGY 2021; 272:113945. [PMID: 33617966 DOI: 10.1016/j.jep.2021.113945] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 01/18/2021] [Accepted: 02/14/2021] [Indexed: 06/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Most Aristolochiaceae plants are prohibited due to aristolochic acid nephropathy (AAN), except Xixin (Asarum spp.). Xixin contains trace amounts of aristolochic acid (AA) and is widely used in Traditional Chinese Medicine. Methylglyoxal and d-lactate are regarded as biomarkers for nephrotoxicity. AIM OF THE STUDY The use of Xixin (Asarum spp.) is essential and controversial. This study aimed to evaluate tubulointerstitial injury and interstitial renal fibrosis by determining urinary methylglyoxal and d-lactate after withdrawal of low-dose AA in a chronic mouse model. MATERIALS AND METHODS C3H/He mice in the AA group (n = 24/group) were given ad libitum access to distilled water containing 3 μg/mL AA (0.5 mg/kg/day) for 56 days and drinking water from days 57 to 84. The severity of tubulointerstitial injury and fibrosis were evaluated using the tubulointerstitial histological score (TIHS) and Masson's trichrome staining. Urinary and serum methylglyoxal were determined by high-performance liquid chromatography (HPLC); urinary d-lactate were determined by column-switching HPLC. RESULTS After AA withdrawal, serum methylglyoxal in the AA group increased from day 56 (429.4 ± 48.3 μg/L) to 84 (600.2 ± 99.9 μg/L), and peaked on day 70 (878.3 ± 171.8 μg/L; p < 0.05); TIHS and fibrosis exhibited similar patterns. Urinary methylglyoxal was high on day 56 (3.522 ± 1.061 μg), declined by day 70 (1.583 ± 0.437 μg) and increased by day 84 (2.390 ± 0.130 μg). Moreover, urinary d-lactate was elevated on day 56 (82.10 ± 18.80 μg) and higher from day 70 (201.10 ± 90.82 μg) to 84 (193.28 ± 61.32 μg). CONCLUSIONS Methylglyoxal is induced after AA-induced tubulointerstitial injury, so methylglyoxal excretion and metabolism may be a detoxification and repair strategy. A low cumulative AA dose is the key factor that limits tubulointerstitial injury and helps to repair. Thus, AA-containing herbs, especially Xixin, should be used at low doses for short durations (less than one month).
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Affiliation(s)
- Chia-En Lin
- School of Pharmacy, College of Pharmacy, Taipei Medical University, No.250 Wu-Hsing Street, Taipei, 110, Taiwan.
| | - Po-Yeh Lin
- School of Pharmacy, College of Pharmacy, Taipei Medical University, No.250 Wu-Hsing Street, Taipei, 110, Taiwan.
| | - Wen-Chi Yang
- School of Pharmacy, College of Pharmacy, Taipei Medical University, No.250 Wu-Hsing Street, Taipei, 110, Taiwan.
| | - Yu-Shen Huang
- School of Pharmacy, College of Pharmacy, Taipei Medical University, No.250 Wu-Hsing Street, Taipei, 110, Taiwan.
| | - Tzu-Yao Lin
- School of Pharmacy, College of Pharmacy, Taipei Medical University, No.250 Wu-Hsing Street, Taipei, 110, Taiwan.
| | - Chien-Ming Chen
- Department of Electro-Optical Engineering, National Taipei University of Technology, Taipei, Taiwan.
| | - Hung-Shing Chen
- Graduate Institute of Electro-optical Engineering, National Taiwan University of Science and Technology, No.43, Keelung Rd., Sec.4, Da'an Dist., Taipei, Taiwan.
| | - Jen-Ai Lee
- School of Pharmacy, College of Pharmacy, Taipei Medical University, No.250 Wu-Hsing Street, Taipei, 110, Taiwan.
| | - Shih-Ming Chen
- School of Pharmacy, College of Pharmacy, Taipei Medical University, No.250 Wu-Hsing Street, Taipei, 110, Taiwan.
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Hepatocyte growth factor ameliorates methylglyoxal-induced peritoneal inflammation and fibrosis in mouse model. Clin Exp Nephrol 2021; 25:935-943. [PMID: 33909175 DOI: 10.1007/s10157-021-02067-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 04/21/2021] [Indexed: 01/20/2023]
Abstract
BACKGROUND Peritoneal dialysis (PD) is essential for patients with end-stage renal disease. Peritoneal fibrosis (PF) is a complex inflammatory, fibrogenic process. No effective treatments are available to prevent these processes. Hepatocyte growth factor (HGF) possesses anti-inflammatory and anti-fibrotic properties. The aim of this study was to analyze whether HGF suppresses MGO-induced peritoneal inflammation and fibrosis in a mouse model. METHODS PF was induced by intraperitoneal (IP) injections of MGO for 14 days. C57/BL/6 mice were divided into three groups: Sham group (only vehicle); Sham + MGO group (PF induced by MGO); and HGF + MGO group (PF mice treated with recombinant human-HGF). PF was assessed from tissue samples by Masson's trichrome staining. Inflammation and fibrosis-associated factors were assessed by immunohistochemistry and quantitative real-time PCR. RESULTS MGO-injected mice showed significant thickening of the submesothelial compact zone with PF. Treatment with HGF significantly reduced PM thickness and suppressed the expression of collagen I and III and α-SMA. Expression of profibrotic and proinflammatory cytokines (TGF-β, TNF-α, IL-1β) was reduced by HGF treatment. The number of macrophages, and M1 and M2 macrophage-related markers, such as CD86, CD206, and CD163, was reduced in HGF + MGO mice. CONCLUSION HGF attenuates MGO-induced PF in mice. Furthermore, HGF treatment reduces myofibroblast and macrophage infiltration, and attenuates the upregulated expression of proinflammatory and profibrotic genes in peritoneal tissues. HGF might be an effective approach to prevent the development of PF in patients undergoing PD.
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Yang CY, Chang PY, Chen JY, Wu BS, Yang AH, Lee OKS. Adipose-derived mesenchymal stem cells attenuate dialysis-induced peritoneal fibrosis by modulating macrophage polarization via interleukin-6. Stem Cell Res Ther 2021; 12:193. [PMID: 33741073 PMCID: PMC7977319 DOI: 10.1186/s13287-021-02270-4] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 03/05/2021] [Indexed: 12/15/2022] Open
Abstract
Background Life-long peritoneal dialysis (PD) as a renal replacement therapy is limited by peritoneal fibrosis. Previous studies showed immunomodulatory and antifibrotic effects of adipose-derived mesenchymal stem cells (ADSCs) on peritoneal fibrosis. However, the role of the peritoneal macrophage in this process remains uninvestigated. Methods We examined the therapeutic effects of ADSC and bone marrow-derived mesenchymal stem cells (BM-MSC) in the rat model of dialysis-induced peritoneal fibrosis using methylglyoxal. In addition, treatment of macrophages with the conditioned medium of ADSC and BM-MSC was performed individually to identify the beneficial component of the stem cell secretome. Results In the in vivo experiments, we found dialysis-induced rat peritoneal fibrosis was attenuated by both ADSC and BM-MSC. Interestingly, ADSC possessed a more prominent therapeutic effect than BM-MSC in ameliorating peritoneal membrane thickening while also upregulating epithelial cell markers in rat peritoneal tissues. The therapeutic effects of ADSC were positively associated with M2 macrophage polarization. In the in vitro experiments, we confirmed that interleukin-6 (IL-6) secreted by MSCs upon transforming growth factor-β1 stimulation promotes M2 macrophage polarization. Conclusions In dialysis-induced peritoneal fibrosis, MSCs are situated in an inflammatory environment of TGF-β1 and secrete IL-6 to polarize macrophages into the M2 phenotype. Our findings reveal a previously unidentified role of tissue macrophage in this antifibrotic process. ADSC has the advantage of abundance and accessibility, making the application values extremely promising. Graphical abstract In dialysis-induced peritoneal fibrosis, peritoneal mesothelial cells secrete transforming growth factor-β1 (TGF-β1) when exposed to methylglyoxal (MGO)-containing peritoneal dialysate. When situated in TGF-β1, the inflammatory environment induces mesenchymal stem cells to secrete interleukin-6 (IL-6), IL-6 polarizes macrophages into the M2 phenotype. The dominant peritoneal tissue M2 macrophages, marked by upregulated Arg-1 expression, account for the attenuation of MGO-induced dedifferentiation of peritoneal mesothelial cells to maintain epithelial integrity.
![]() Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02270-4.
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Affiliation(s)
- Chih-Yu Yang
- Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, 2F, Shou-Ren Bldg., No.155, Sec.2, Li-Nong St., Beitou Dist, Taipei, 11221, Taiwan. .,Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan. .,Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, 11217, Taiwan. .,Stem Cell Research Center, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan. .,Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B), Hsinchu, 30010, Taiwan.
| | - Pu-Yuan Chang
- Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, 2F, Shou-Ren Bldg., No.155, Sec.2, Li-Nong St., Beitou Dist, Taipei, 11221, Taiwan
| | - Jun-Yi Chen
- Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, 2F, Shou-Ren Bldg., No.155, Sec.2, Li-Nong St., Beitou Dist, Taipei, 11221, Taiwan
| | - Bo-Sheng Wu
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan
| | - An-Hang Yang
- Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, 2F, Shou-Ren Bldg., No.155, Sec.2, Li-Nong St., Beitou Dist, Taipei, 11221, Taiwan.,Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan.,Department of Pathology, Taipei Veterans General Hospital, Taipei, 11217, Taiwan
| | - Oscar Kuang-Sheng Lee
- Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, 2F, Shou-Ren Bldg., No.155, Sec.2, Li-Nong St., Beitou Dist, Taipei, 11221, Taiwan.,Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan.,Stem Cell Research Center, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan.,Department of Orthopedics, China Medical University Hospital, Taichung, 40447, Taiwan
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Kang DH. Loosening of the mesothelial barrier as an early therapeutic target to preserve peritoneal function in peritoneal dialysis. Kidney Res Clin Pract 2020; 39:136-144. [PMID: 32576713 PMCID: PMC7321674 DOI: 10.23876/j.krcp.20.052] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 05/08/2020] [Accepted: 05/11/2020] [Indexed: 12/21/2022] Open
Abstract
Phenotype transition of peritoneal mesothelial cells (MCs) including the epithelial-to-mesenchymal transition (EMT) is regarded as an early mechanism of peritoneal dysfunction and fibrosis in peritoneal dialysis (PD), producing proinflammatory and pro-fibrotic milieu in the intra-peritoneal cavity. Loosening of intercellular tight adhesion between adjacent MCs as an initial process of EMT creates the environment where mesothelium and submesothelial tissue are more vulnerable to the composition of bio-incompatible dialysates, reactive oxygen species, and inflammatory cytokines. In addition, down-regulation of epithelial cell markers such as E-cadherin facilitates de novo acquisition of mesenchymal phenotypes in MCs and production of extracellular matrices. Major mechanisms underlying the EMT of MCs include induction of oxidative stress, pro-inflammatory cytokines, endoplasmic reticulum stress and activation of the local renin-angiotensin system. Another mechanism of peritoneal EMT is mitigation of intrinsic defense mechanisms such as the peritoneal antioxidant system and anti-fibrotic peptide production in the peritoneal cavity. In addition to use of less bio-incompatible dialysates and optimum treatment of peritonitis in PD, therapies to prevent or alleviate peritoneal EMT have demonstrated a favorable effect on peritoneal function and structure, suggesting that EMT can be an early interventional target to preserve peritoneal integrity.
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Affiliation(s)
- Duk-Hee Kang
- Division of Nephrology, Department of Internal Medicine, Ewha Womans University School of Medicine, Ewha Medical Research Center, Seoul, Republic of Korea
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Hirahara I, Kusano E, Jin D, Takai S. Hypermetabolism of glutathione, glutamate and ornithine via redox imbalance in methylglyoxal-induced peritoneal injury rats. J Biochem 2020; 167:185-194. [PMID: 31593282 DOI: 10.1093/jb/mvz077] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Accepted: 09/17/2019] [Indexed: 11/13/2022] Open
Abstract
Peritoneal dialysis (PD) is a blood purification treatment for patients with reduced renal function. However, the peritoneum is exposed to oxidative stress during PD and long-term PD results in peritoneal damage, leading to the termination of PD. Methylglyoxal (MGO) contained in commercial PD fluids is a source of strong oxidative stress. The aim of this study was to clarify the mechanism of MGO-induced peritoneal injury using metabolome analysis in rats. We prepared peritoneal fibrosis rats by intraperitoneal administration of PD fluids containing MGO for 21 days. As a result, MGO-induced excessive proliferation of mesenchymal cells with an accumulation of advanced glycation end-products (AGEs) at the surface of the thickened peritoneum in rats. The effluent levels of methionine sulfoxide, an oxidative stress marker and glutathione peroxidase activity were increased in the MGO-treated rats. The levels of glutathione, glutamate, aspartate, ornithine and AGEs were also increased in these rats. MGO upregulated the gene expression of transporters and enzymes related to the metabolism of glutathione, glutamate and ornithine in the peritoneum. These results suggest that MGO may induce peritoneal injury with mesenchymal cell proliferation via increased redox metabolism, directly or through the formation of AGEs during PD.
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Affiliation(s)
- Ichiro Hirahara
- Department of Innovative Medicine, Graduate School of Medicine, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 568-8686
| | - Eiji Kusano
- JCHO Utsunomiya Hospital, 11-17 Minamitakasago-chou, Utsunomiya, Tochigi 321-0143, Japan
| | - Denan Jin
- Department of Innovative Medicine, Graduate School of Medicine, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 568-8686
| | - Shinji Takai
- Department of Innovative Medicine, Graduate School of Medicine, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 568-8686
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Crucial Role of NLRP3 Inflammasome in the Development of Peritoneal Dialysis-related Peritoneal Fibrosis. Sci Rep 2019; 9:10363. [PMID: 31316105 PMCID: PMC6637185 DOI: 10.1038/s41598-019-46504-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Accepted: 06/27/2019] [Indexed: 12/22/2022] Open
Abstract
Long-term peritoneal dialysis (PD) therapy leads to peritoneal inflammation and fibrosis. However, the mechanism underlying PD-related peritoneal inflammation and fibrosis remains unclear. NLRP3 inflammasome regulates the caspase-1-dependent release of interleukin-1β and mediates inflammation in various diseases. Here, we investigated the role of NLRP3 inflammasome in a murine model of PD-related peritoneal fibrosis induced by methylglyoxal (MGO). Inflammasome-related proteins were upregulated in the peritoneum of MGO-treated mice. MGO induced parietal and visceral peritoneal fibrosis in wild-type mice, which was significantly reduced in mice deficient in NLRP3, ASC, and interleukin-1β (IL-1β). ASC deficiency reduced the expression of inflammatory cytokines and fibrotic factors, and the infiltration of macrophages. However, myeloid cell-specific ASC deficiency failed to inhibit MGO-induced peritoneal fibrosis. MGO caused hemorrhagic ascites, fibrin deposition, and plasminogen activator inhibitor-1 upregulation, but all of these manifestations were inhibited by ASC deficiency. Furthermore, in vitro experiments showed that MGO induced cell death via the generation of reactive oxygen species in vascular endothelial cells, which was inhibited by ASC deficiency. Our results showed that endothelial NLRP3 inflammasome contributes to PD-related peritoneal inflammation and fibrosis, and provide new insights into the mechanisms underlying the pathogenesis of this disorder.
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Tamura R, Doi S, Nakashima A, Sasaki K, Maeda K, Ueno T, Masaki T. Inhibition of the H3K4 methyltransferase SET7/9 ameliorates peritoneal fibrosis. PLoS One 2018; 13:e0196844. [PMID: 29723250 PMCID: PMC5933785 DOI: 10.1371/journal.pone.0196844] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Accepted: 04/20/2018] [Indexed: 11/18/2022] Open
Abstract
Transforming growth factor-β1 (TGF-β1) is a major mediator of peritoneal fibrosis and reportedly affects expression of the H3K4 methyltransferase, SET7/9. SET7/9-induced H3K4 mono-methylation (H3K4me1) critically activates transcription of fibrosis-related genes. In this study, we examined the effect of SET7/9 inhibition on peritoneal fibrosis in mice and in human peritoneal mesothelial cells (HPMCs). We also examined SET7/9 expression in nonadherent cells isolated from the effluent of peritoneal dialysis (PD) patients. Murine peritoneal fibrosis was induced by intraperitoneal injection of methylglyoxal (MGO) into male C57/BL6 mice over 21 days. Sinefungin, a SET7/9 inhibitor, was administered subcutaneously just before MGO injection (10 mg/kg). SET7/9 expression was elevated in both MGO-injected mice and nonadherent cells isolated from the effluent of PD patients. SET7/9 expression was positively correlated with dialysate/plasma ratio of creatinine in PD patients. Sinefungin was shown immunohistochemically to suppress expression of mesenchymal cells and collagen deposition, accompanied by decreased H3K4me1 levels. Peritoneal equilibration tests showed that sinefungin attenuated the urea nitrogen transport rate from plasma and the glucose absorption rate from the dialysate. In vitro, sinefungin suppressed TGF-β1-induced expression of fibrotic markers and inhibited H3K4me1. These findings suggest that inhibiting the H3K4 methyltransferase SET7/9 ameliorates peritoneal fibrosis.
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Affiliation(s)
- Ryo Tamura
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan
| | - Shigehiro Doi
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan
- * E-mail:
| | - Ayumu Nakashima
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan
| | - Kensuke Sasaki
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan
| | - Kazuya Maeda
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan
| | - Toshinori Ueno
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan
| | - Takao Masaki
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan
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Masola V, Granata S, Bellin G, Gambaro G, Onisto M, Rugiu C, Lupo A, Zaza G. Specific heparanase inhibition reverses glucose-induced mesothelial-to-mesenchymal transition. Nephrol Dial Transplant 2018; 32:1145-1154. [PMID: 28064160 DOI: 10.1093/ndt/gfw403] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2016] [Accepted: 10/10/2016] [Indexed: 01/19/2023] Open
Abstract
Background Epithelial-to-mesenchymal transition (EMT) of peritoneal mesothelial cells induced by high glucose (HG) levels is a major biological mechanism leading to myofibroblast accumulation in the omentum of patients on peritoneal dialysis (PD). Heparanase (HPSE), an endoglycosidase that cleaves heparan sulfate chains, is involved in the EMT of several cell lines, and may have a major role in this pro-fibrotic process potentially responsible for the failure of dialysis. Its specific inhibition may therefore plausibly minimize this pathological condition. Methods An in vitro study employing several biomolecular strategies was conducted to assess the role of HPSE in the HG-induced mesothelial EMT process, and to measure the effects of its specific inhibition by SST0001, a N-acetylated glycol-split heparin with a strong anti-HPSE activity. Rat mesothelial cells were grown for 6 days in HG (200 mM) culture medium with or without SST0001. Then EMT markers (VIM, α-SMA, TGF-β) and vascular endothelial growth factor (VEGF) (a factor involved in neoangiogenesis) were measured by real-time PCR and immunofluorescence/western blotting. As a functional analysis, trans-epithelial resistance (TER) and permeability to albumin were also measured in our in vitro model using a Millicell-ERS ohmmeter and a spectrophotometer, respectively. Results Our results showed that 200 mM of glucose induced a significant gene and protein up-regulation of VEGF and all EMT markers after 6 days of culture. Intriguingly, adding SST0001 on day 3 reversed these biological and cellular effects. HPSE inhibition also restored the normal TER and permeability lost during the HG treatment. Conclusion Taken together, our data confirm that HG can induce EMT of mesothelial cells, and that HPSE plays a central part in this process. Our findings also suggest that pharmacological HPSE inhibition could prove a valuable therapeutic tool for minimizing fibrosis and avoiding a rapid decline in the efficacy of dialysis in patients on PD, though clinical studies and/or trials would be needed to confirm the clinical utility of this treatment.
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Affiliation(s)
- Valentina Masola
- Renal Unit, Department of Medicine, Verona University Hospital, Verona, Italy
| | - Simona Granata
- Renal Unit, Department of Medicine, Verona University Hospital, Verona, Italy
| | - Gloria Bellin
- Renal Unit, Department of Medicine, Verona University Hospital, Verona, Italy
| | - Giovanni Gambaro
- Nephrology and Dialysis Division, Columbus-Gemelli Hospital, Catholic University School of Medicine, Rome, Italy
| | - Maurizio Onisto
- Department of Biomedical Sciences, University of Padova, Padova, Italy
| | - Carlo Rugiu
- Renal Unit, Department of Medicine, Verona University Hospital, Verona, Italy
| | - Antonio Lupo
- Renal Unit, Department of Medicine, Verona University Hospital, Verona, Italy
| | - Gianluigi Zaza
- Renal Unit, Department of Medicine, Verona University Hospital, Verona, Italy
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Acidic organelles mediate TGF-β1-induced cellular fibrosis via (pro)renin receptor and vacuolar ATPase trafficking in human peritoneal mesothelial cells. Sci Rep 2018; 8:2648. [PMID: 29422602 PMCID: PMC5805675 DOI: 10.1038/s41598-018-20940-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Accepted: 01/26/2018] [Indexed: 01/30/2023] Open
Abstract
TGF-β1, which can cause renal tubular injury through a vacuolar-type H+-ATPase (V-ATPase)-mediated pathway, is induced by the glucose degradation product methylglyoxal to yield peritoneal injury and fibrosis. The present study investigated the roles of V-ATPase and its accessory protein, the (pro)renin receptor, in peritoneal fibrosis during peritoneal dialysis. Rats daily administered 20 mM methylglyoxal intraperitoneally developed significant peritoneal fibrosis after 7 days with increased expression of TGF-β and V-ATPase, which was reduced by the inhibition of V-ATPase with co-administration of 100 mM bafilomycin A1. The (pro)renin receptor and V-ATPase were expressed in acidic organelles and cell membranes of human peritoneal mesothelial cells. TGF-β1 upregulated the expression of collagens, α-SMA, and EDA-fibronectin, together with ERK1/2 phosphorylation, which was reduced by inhibition of V-ATPase, (pro)renin receptor, or the MAPK pathway. Fibronectin and the soluble (pro)renin receptor were excreted from cells by acidic organelle trafficking in response to TGF-β1; this excretion was also suppressed by inhibition of V-ATPase. Soluble (pro)renin receptor concentrations in effluents of patients undergoing peritoneal dialysis were associated with the dialysate-to-plasma ratio of creatinine. Together, these results demonstrate a novel fibrosis mechanism through the (pro)renin receptor and V-ATPase in the acidic organelles of peritoneal mesothelial cells.
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Antognelli C, Talesa VN. Glyoxalases in Urological Malignancies. Int J Mol Sci 2018; 19:ijms19020415. [PMID: 29385039 PMCID: PMC5855637 DOI: 10.3390/ijms19020415] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Revised: 01/25/2018] [Accepted: 01/26/2018] [Indexed: 12/16/2022] Open
Abstract
Urological cancers include a spectrum of malignancies affecting organs of the reproductive and/or urinary systems, such as prostate, kidney, bladder, and testis. Despite improved primary prevention, detection and treatment, urological cancers are still characterized by an increasing incidence and mortality worldwide. While advances have been made towards understanding the molecular bases of these diseases, a complete understanding of the pathological mechanisms remains an unmet research goal that is essential for defining safer pharmacological therapies and prognostic factors, especially for the metastatic stage of these malignancies for which no effective therapies are currently being used. Glyoxalases, consisting of glyoxalase 1 (Glo1) and glyoxalase 2 (Glo2), are enzymes that catalyze the glutathione-dependent metabolism of cytotoxic methylglyoxal (MG), thus protecting against cellular damage and apoptosis. They are generally overexpressed in numerous cancers as a survival strategy by providing a safeguard through enhancement of MG detoxification. Increasing evidence suggests that glyoxalases, especially Glo1, play an important role in the initiation and progression of urological malignancies. In this review, we highlight the critical role of glyoxalases as regulators of tumorigenesis in the prostate through modulation of various critical signaling pathways, and provide an overview of the current knowledge on glyoxalases in bladder, kidney and testis cancers. We also discuss the promise and challenges for Glo1 inhibitors as future anti-prostate cancer (PCa) therapeutics and the potential of glyoxalases as biomarkers for PCa diagnosis.
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Affiliation(s)
- Cinzia Antognelli
- Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
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Inhibition of GLO1 in Glioblastoma Multiforme Increases DNA-AGEs, Stimulates RAGE Expression, and Inhibits Brain Tumor Growth in Orthotopic Mouse Models. Int J Mol Sci 2018; 19:ijms19020406. [PMID: 29385725 PMCID: PMC5855628 DOI: 10.3390/ijms19020406] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2017] [Revised: 01/22/2018] [Accepted: 01/26/2018] [Indexed: 12/22/2022] Open
Abstract
Cancers that exhibit the Warburg effect may elevate expression of glyoxylase 1 (GLO1) to detoxify the toxic glycolytic byproduct methylglyoxal (MG) and inhibit the formation of pro-apoptotic advanced glycation endproducts (AGEs). Inhibition of GLO1 in cancers that up-regulate glycolysis has been proposed as a therapeutic targeting strategy, but this approach has not been evaluated for glioblastoma multiforme (GBM), the most aggressive and difficult to treat malignancy of the brain. Elevated GLO1 expression in GBM was established in patient tumors and cell lines using bioinformatics tools and biochemical approaches. GLO1 inhibition in GBM cell lines and in an orthotopic xenograft GBM mouse model was examined using both small molecule and short hairpin RNA (shRNA) approaches. Inhibition of GLO1 with S-(p-bromobenzyl) glutathione dicyclopentyl ester (p-BrBzGSH(Cp)2) increased levels of the DNA-AGE N2-1-(carboxyethyl)-2′-deoxyguanosine (CEdG), a surrogate biomarker for nuclear MG exposure; substantially elevated expression of the immunoglobulin-like receptor for AGEs (RAGE); and induced apoptosis in GBM cell lines. Targeting GLO1 with shRNA similarly increased CEdG levels and RAGE expression, and was cytotoxic to glioma cells. Mice bearing orthotopic GBM xenografts treated systemically with p-BrBzGSH(Cp)2 exhibited tumor regression without significant off-target effects suggesting that GLO1 inhibition may have value in the therapeutic management of these drug-resistant tumors.
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Igarashi Y, Hoshino T, Ookawara S, Ishibashi K, Morishita Y. Nano-sized carriers in gene therapy for peritoneal fibrosis in vivo. NANO REVIEWS & EXPERIMENTS 2017; 8:1331100. [PMID: 30410706 PMCID: PMC6167028 DOI: 10.1080/20022727.2017.1331100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Accepted: 05/11/2017] [Indexed: 11/07/2022]
Abstract
Peritoneal fibrosis is a crucial complication in patients receiving peritoneal dialysis. It is a major pathological feature of peritoneal membrane failure, which leads to withdrawal of peritoneal dialysis. No specific therapy has yet been established for the treatment of peritoneal fibrosis. However, gene therapy may be a viable option, and various nano-sized carriers, including viral and non-viral vectors, have been shown to enhance the delivery and efficacy of gene therapy for peritoneal fibrosis in vivo. This review focuses on the use of nano-sized carriers in gene therapy of peritoneal fibrosis in vivo.
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Affiliation(s)
- Yusuke Igarashi
- Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Tochigi, Japan
| | - Taro Hoshino
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Susumu Ookawara
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Kenichi Ishibashi
- Department of Medical Physiology, Meiji Pharmaceutical University, Tokyo, Japan
| | - Yoshiyuki Morishita
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
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15
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Yang CY, Chau YP, Chen A, Lee OKS, Tarng DC, Yang AH. Targeting cannabinoid signaling for peritoneal dialysis-induced oxidative stress and fibrosis. World J Nephrol 2017; 6:111-118. [PMID: 28540200 PMCID: PMC5424432 DOI: 10.5527/wjn.v6.i3.111] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Revised: 01/20/2017] [Accepted: 02/20/2017] [Indexed: 02/06/2023] Open
Abstract
Long-term exposure to bioincompatible peritoneal dialysis (PD) solutions frequently results in peritoneal fibrosis and ultrafiltration failure, which limits the life-long use of and leads to the cessation of PD therapy. Therefore, it is important to elucidate the pathogenesis of peritoneal fibrosis in order to design therapeutic strategies to prevent its occurrence. Peritoneal fibrosis is associated with a chronic inflammatory status as well as an elevated oxidative stress (OS) status. Beyond uremia per se, OS also results from chronic exposure to high glucose load, glucose degradation products, advanced glycation end products, and hypertonic stress. Therapy targeting the cannabinoid (CB) signaling pathway has been reported in several chronic inflammatory diseases with elevated OS. We recently reported that the intra-peritoneal administration of CB receptor ligands, including CB1 receptor antagonists and CB2 receptor agonists, ameliorated dialysis-related peritoneal fibrosis. As targeting the CB signaling pathway has been reported to be beneficial in attenuating the processes of several chronic inflammatory diseases, we reviewed the interaction among the cannabinoid system, inflammation, and OS, through which clinicians ultimately aim to prolong the peritoneal survival of PD patients.
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Ito Y, Kinashi H, Katsuno T, Suzuki Y, Mizuno M. Peritonitis-induced peritoneal injury models for research in peritoneal dialysis review of infectious and non-infectious models. RENAL REPLACEMENT THERAPY 2017. [DOI: 10.1186/s41100-017-0100-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
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Hirata H, Fumoto S, Miyamoto H, Nakashima M, Nakayama M, Nishida K. Evaluation for Peritoneal Injury at an Early Stage Using Dual Macromolecular Markers. Biol Pharm Bull 2017; 39:1581-1587. [PMID: 27725434 DOI: 10.1248/bpb.b15-01042] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Long-term peritoneal dialysis (PD) frequently produces morphological and functional changes of the peritoneum, making continuation of PD difficult. Therefore, it is necessary to evaluate peritoneal injury at an early stage and develop appropriate therapies. The aims of the present study were to evaluate peritoneal injury at an early stage and assess a drug for prevention of peritoneal injury using our previously developed novel evaluation method. Peritoneal injury was induced in model animals by intraperitoneal injection of methylglyoxal (MGO) for 1 to 5 consecutive days or chlorhexidine digluconate (CG) for 1 to 14 consecutive days. Tetramethylrhodamine-dextran (RD)-10 and fluorescein isothiocyanate-dextran (FD)-2000 were then injected into the peritoneal cavity and recovered after 120 min to evaluate peritoneal injury. The ratio of the concentration of RD-10 to FD-2000 (RD-10/FD-2000 ratio) significantly decreased in animals that had been treated with MGO or CG for 1 d. Moreover, the RD-10/FD-2000 ratio significantly increased in CG- and thalidomide-treated animals. The RD-10/FD-2000 ratio can be used to evaluate peritoneal injury at an early stage and assess the drug efficacy of thalidomide for prevention of peritoneal injury. This study will contribute to the development of therapeutic treatments for peritoneal injury.
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Affiliation(s)
- Haruna Hirata
- Graduate School of Biomedical Sciences, Nagasaki University
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Mori Y, Kakuta T, Miyakogawa T, Takekoshi S, Yuzawa H, Kobayashi H, Kawakami A, Miyata T, Fukagawa M. Effect of Scavenging Circulating Reactive Carbonyls by Oral Pyridoxamine in Uremic Rats on Peritoneal Dialysis. Ther Apher Dial 2016; 20:645-654. [PMID: 27620210 DOI: 10.1111/1744-9987.12446] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Revised: 04/06/2016] [Accepted: 04/12/2016] [Indexed: 11/30/2022]
Abstract
Pyridoxamine, a reactive carbonyl (RCO) scavenger, can ameliorate peritoneal deterioration in uremic peritoneal dialysis (PD) rats when given via dialysate. We examined the effects of scavenging circulating RCOs by oral pyridoxamine. Rats underwent nephrectomy and 3 weeks of twice daily PD either alone or with once daily oral pyridoxamine. PD solution was supplemented with methylglyoxal, a major glucose-derived RCO, to quench intraperitoneal pyridoxamine. Oral pyridoxamine achieved comparable blood and dialysate pyridoxamine concentrations, suppressed pentosidine accumulation in the blood but not in the mesenterium or dialysate, and reduced the increases in small solute transport and mesenteric vessel densities, with no effects on submesothelial matrix layer thickening or serum creatinine. Thus, reducing circulating RCOs by giving oral pyridoxamine with PD provides limited peritoneal protection. However, orally given pyridoxamine efficiently reaches the peritoneal cavity and would eliminate intraperitoneal RCOs. Oral pyridoxamine is more clinically favorable and may be as protective as intraperitoneal administration.
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Affiliation(s)
- Yoshitaka Mori
- Department of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Isehara, Japan.,Unit of Translational Medicine, Department of Endocrinology and Metabolism, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Takatoshi Kakuta
- Department of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Isehara, Japan.,Department of Nephrology, Endocrinology and Metabolism, Tokai University Hachioji Hospital, Hachioji, Tokyo, Japan
| | - Takayo Miyakogawa
- Department of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Isehara, Japan
| | - Susumu Takekoshi
- Division of Basic Molecular Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Hiroko Yuzawa
- Department of Neurology, Tokai University School of Medicine, Isehara, Japan
| | - Hiroyuki Kobayashi
- Department of Clinical Pharmacology, Tokai University School of Medicine, Isehara, Japan
| | - Atsushi Kawakami
- Unit of Translational Medicine, Department of Endocrinology and Metabolism, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Toshio Miyata
- United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Masafumi Fukagawa
- Department of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Isehara, Japan
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Nagai T, Doi S, Nakashima A, Irifuku T, Sasaki K, Ueno T, Masaki T. Linagliptin Ameliorates Methylglyoxal-Induced Peritoneal Fibrosis in Mice. PLoS One 2016; 11:e0160993. [PMID: 27513960 PMCID: PMC4981421 DOI: 10.1371/journal.pone.0160993] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Accepted: 07/28/2016] [Indexed: 12/14/2022] Open
Abstract
Recent studies have reported increases of methylglyoxal (MGO) in peritoneal dialysis patients, and that MGO-mediated inflammation plays an important role in the development of peritoneal fibrosis through production of transforming growth factor-β1 (TGF-β1). Linagliptin, a dipeptidyl peptidase-4 inhibitor, exerts anti-inflammatory effects independent of blood glucose levels. In this study, we examined whether linagliptin suppresses MGO-induced peritoneal fibrosis in mice. Male C57/BL6 mice were divided into three groups: control, MGO injection plus saline, and MGO injection plus linagliptin (n = 6 per group). Peritoneal fibrosis was induced by daily intraperitoneal injection of saline containing 40 mmol/L MGO for 21 days. Saline was administered intraperitoneally to the control group. Linagliptin (10 mg/kg) or saline were administrated by once-daily oral gavage from 3 weeks before starting MGO injections. Immunohistochemical staining revealed that linagliptin suppressed expression of α-smooth muscle actin and fibroblast-specific protein-1, deposition of type I and III collagen, and macrophage (F4/80) infiltration. Peritoneal equilibration testing showed improved peritoneal functions in mice treated with linagliptin. Peritoneal injection of MGO increased plasma levels of glucagon-like peptide-1 (GLP-1) in mice, and a further increase was observed in linagliptin-treated mice. Although MGO increased plasma glucose levels, linagliptin did not decrease plasma glucose levels. Moreover, linagliptin reduced the TGF-β1 concentration in the peritoneal fluid of MGO-treated mice. GLP-1 receptor (GLP-1R) was expressed in monocytes/macrophages and linagliptin suppressed GLP-1R expression in MGO-injected mice. These results suggest that oral administration of linagliptin ameliorates MGO-induced peritoneal fibrosis.
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Affiliation(s)
- Takuo Nagai
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan
| | - Shigehiro Doi
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan
- * E-mail:
| | - Ayumu Nakashima
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan
| | - Taisuke Irifuku
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan
| | - Kensuke Sasaki
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan
| | - Toshinori Ueno
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan
| | - Takao Masaki
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan
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20
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Hirahara I, Kusano E, Morishita Y, Inoue M, Akimoto T, Saito O, Muto S, Nagata D. Matrix metalloproteinase-2 as a superior biomarker for peritoneal deterioration in peritoneal dialysis. World J Nephrol 2016; 5:204-212. [PMID: 26981446 PMCID: PMC4777793 DOI: 10.5527/wjn.v5.i2.204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Revised: 11/05/2015] [Accepted: 12/20/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the efficacy of effluent biomarkers for peritoneal deterioration with functional decline in peritoneal dialysis (PD).
METHODS: From January 2005 to March 2013, the subjects included 218 PD patients with end-stage renal disease at 18 centers. Matrix metalloproteinase-2 (MMP-2), interleukin-6 (IL-6), hyaluronan, and cancer antigen 125 (CA125) in peritoneal effluent were quantified with enzyme-linked immunosorbent assay. Peritoneal solute transport rate was assessed by peritoneal equilibration test (PET) to estimate peritoneal deterioration.
RESULTS: The ratio of the effluent level of creatinine (Cr) obtained 4 h after injection (D) to that of plasma was correlated with the effluent levels of MMP-2 (ρ = 0.74, P < 0.001), IL-6 (ρ = 0.46, P < 0.001), and hyaluronan (ρ = 0.27, P < 0.001), but not CA125 (ρ = 0.13, P = 0.051). The area under receiver operating characteristic curve for the effluent levels of MMP-2, IL-6, and hyaluronan against high PET category were 0.90, 0.78, 0.62, and 0.51, respectively. No patient developed new-onset encapsulating peritoneal sclerosis for at least 1.5 years after peritoneal effluent sampling.
CONCLUSION: The effluent MMP-2 level most closely reflected peritoneal solute transport rate. MMP-2 can be a reliable indicator of peritoneal deterioration with functional decline.
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21
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Morishita Y, Yoshizawa H, Watanabe M, Imai R, Imai T, Hirahara I, Akimoto T, Ookawara S, Muto S, Nagata D. MicroRNA expression profiling in peritoneal fibrosis. Transl Res 2016; 169:47-66. [PMID: 26616819 DOI: 10.1016/j.trsl.2015.10.009] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2015] [Revised: 10/28/2015] [Accepted: 10/29/2015] [Indexed: 12/22/2022]
Abstract
Peritoneal fibrosis (PF) is an intractable complication leading to peritoneal membrane failure in peritoneal dialysis (PD). The aim of this study was to identify microRNAs (miRNAs) involved in PF. Peritoneal tissue from a PF rat model was screened for miRNA expression using microarray analysis. The expression levels of differentially expressed miRNAs were evaluated in serum and drained dialysate and associated with peritoneal membrane functions, as measured by the peritoneal equilibrium test in 33 PD patients. Furthermore, an miRNA inhibitor (anti-miRNA-21-5p locked nucleic acid (LNA): anti-miRNA-21-LNA) was intraperitoneally injected to PF model mice to investigate its effects on PF. The initial profiling study of PF rat peritoneal tissue identified 6 miRNAs (miRNA-142-3p, miRNA-21-5p, miRNA-221-3p, miRNA-223-3p, miRNA-34a-5p, and miRNA-327) whose expression was increased more than 2-fold and no miRNAs whose expression was decreased more than half. Among them, serum levels of miRNA-21-5p, miRNA-221-3p, and miRNA-327 and drained dialysate levels of miRNA-221-3p and miRNA-34a-5p were significantly correlated with peritoneal membrane functions in PD patients. Anti-miRNA-21-LNA significantly inhibited miRNA-21-5p expression in the PF mouse peritoneum, inhibited peritoneal fibrous thickening, and maintained peritoneal membrane functions. These results suggest that several miRNAs are involved in PF and that they may be useful as novel diagnostic biomarkers and therapeutic targets for PF.
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Affiliation(s)
- Yoshiyuki Morishita
- Division of Nephrology, Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Omiya, Saitama, Japan.
| | - Hiromichi Yoshizawa
- Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke City, Tochigi, Tochigi, Japan
| | - Minami Watanabe
- Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke City, Tochigi, Tochigi, Japan
| | - Reika Imai
- Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke City, Tochigi, Tochigi, Japan
| | - Toshimi Imai
- Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke City, Tochigi, Tochigi, Japan
| | - Ichiro Hirahara
- Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke City, Tochigi, Tochigi, Japan
| | - Tetsu Akimoto
- Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke City, Tochigi, Tochigi, Japan
| | - Susumu Ookawara
- Division of Nephrology, Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Omiya, Saitama, Japan
| | - Shigeaki Muto
- Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke City, Tochigi, Tochigi, Japan
| | - Daisuke Nagata
- Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke City, Tochigi, Tochigi, Japan
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Effluent Tenascin-C Levels Reflect Peritoneal Deterioration in Peritoneal Dialysis: MAJOR IN PD Study. BIOMED RESEARCH INTERNATIONAL 2015; 2015:241098. [PMID: 26770971 PMCID: PMC4684852 DOI: 10.1155/2015/241098] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Revised: 09/04/2015] [Accepted: 10/29/2015] [Indexed: 01/03/2023]
Abstract
Peritoneal deterioration causing structural changes and functional decline is a major complication of peritoneal dialysis (PD). The aim of this study was to explore effluent biomarkers reflecting peritoneal deterioration. In an animal study, rats were intraperitoneally administered with PD fluids adding 20 mM methylglyoxal (MGO) or 20 mM formaldehyde (FA) every day for 21 days. In the MGO-treated rats, tenascin-C (TN-C) levels in the peritoneal effluents were remarkably high and a cluster of TN-C-positive mesothelial cells with epithelial-to-mesenchymal transition- (EMT-) like change excessively proliferated at the peritoneal surface, but not in the FA-treated rats. Effluent matrix metalloproteinase-2 (MMP-2) levels increased in both the MGO- and FA-treated rats. In a clinical study at 18 centers between 2006 and 2013, effluent TN-C and MMP-2 levels were quantified in 182 PD patients with end-stage renal disease. Peritoneal function was estimated using the peritoneal equilibration test (PET). From the PET results, the D/P Cr ratio was correlated with effluent levels of TN-C (ρ = 0.57, p < 0.001) and MMP-2 (ρ = 0.73, p < 0.001). We suggest that TN-C in the effluents may be a diagnostic marker for peritoneal deterioration with EMT-like change in mesothelial cells in PD.
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Onishi A, Akimoto T, Urabe M, Hirahara I, Muto S, Ozawa K, Nagata D, Kusano E. Attenuation of methylglyoxal-induced peritoneal fibrosis: immunomodulation by interleukin-10. J Transl Med 2015; 95:1353-62. [PMID: 26367488 DOI: 10.1038/labinvest.2015.110] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2015] [Revised: 04/28/2015] [Accepted: 05/19/2015] [Indexed: 01/07/2023] Open
Abstract
Peritoneal fibrosis (PF), a serious pathophysiology of peritoneal dialysis (PD), is implicated in various types of chronic inflammation. In the present study, we examined the benefits of interleukin (IL)-10, which exerts anti-inflammatory effects, in an experimental rat model of methylglyoxal (MGO)-induced PF. We injected an adeno-associated virus (AAV) vector encoding rat IL-10 or enhanced green fluorescent protein (GFP) into male Sprague-Dawley rats at 6 weeks of age. Four weeks later, the rats received continuous peritoneal injections of conventional PD fluid (PDF) with MGO for 3 weeks. Then, the peritoneal histology and the expression levels of fibrogenic mediators and proinflammatory cytokines were analyzed. The rats demonstrating persistent IL-10 expression showed significantly reduced fibrous peritoneal thickening compared with those with GFP expression. The infiltration of macrophages, the expression of tumor necrosis factor-α, IL-1β, IL-6, transforming growth factor-β1, Snail, and matrix metalloproteinase 2 genes as well as the proliferation of mesenchymal-like mesothelial cells augmented by MGO were all significantly suppressed by IL-10 expression. IL-10 also abrogated the extent of MGO-induced bowel adhesions mimicking a cocoon-like mass. Our findings provide valuable insight into the potential benefit of immunomodulation with IL-10 as one potentially effective therapeutic strategy for preventing the onset of peritoneal injury resulting in PF.
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Affiliation(s)
- Akira Onishi
- Division of Nephrology, Department of Medicine, Jichi Medical University, Tochigi, Japan
| | - Tetsu Akimoto
- Division of Nephrology, Department of Medicine, Jichi Medical University, Tochigi, Japan
| | - Masashi Urabe
- Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan
| | - Ichiro Hirahara
- Division of Nephrology, Department of Medicine, Jichi Medical University, Tochigi, Japan
| | - Shigeaki Muto
- Division of Nephrology, Department of Medicine, Jichi Medical University, Tochigi, Japan
| | - Keiya Ozawa
- Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan
| | - Daisuke Nagata
- Division of Nephrology, Department of Medicine, Jichi Medical University, Tochigi, Japan
| | - Eiji Kusano
- Division of Nephrology, Department of Medicine, Jichi Medical University, Tochigi, Japan
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Liu Y, Dong Z, Liu H, Zhu J, Liu F, Chen G. Transition of mesothelial cell to fibroblast in peritoneal dialysis: EMT, stem cell or bystander? Perit Dial Int 2015; 35:14-25. [PMID: 25700459 DOI: 10.3747/pdi.2014.00188] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Long-term peritoneal dialysis (PD) can lead to fibrotic changes in the peritoneum, characterized by loss of mesothelial cells (MCs) and thickening of the submesothelial area with an accumulation of collagen and myofibroblasts. The origin of myofibroblasts is a central question in peritoneal fibrosis that remains unanswered at present. Numerous clinical and experimental studies have suggested that MCs, through epithelial-mesenchymal transition (EMT), contribute to the pool of peritoneal myofibroblasts. However, recent work has placed significant doubts on the paradigm of EMT in organ fibrogenesis (in the kidney particularly), highlighting the need to reconsider the role of EMT in the generation of myofibroblasts in peritoneal fibrosis. In particular, selective cell isolation and lineage-tracing experiments have suggested the existence of progenitor cells in the peritoneum, which are able to switch to fibroblast-like cells when stimulated by the local environment. These findings highlight the plastic nature of MCs and its contribution to peritoneal fibrogenesis. In this review, we summarize the key findings and caveats of EMT in organ fibrogenesis, with a focus on PD-related peritoneal fibrosis, and discuss the potential of peritoneal MCs as a source of myofibroblasts.
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Affiliation(s)
- Yu Liu
- Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, PR China; Department of Cellular Biology and Anatomy, Georgia Regents University and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia, USA
| | - Zheng Dong
- Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, PR China; Department of Cellular Biology and Anatomy, Georgia Regents University and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia, USA Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, PR China; Department of Cellular Biology and Anatomy, Georgia Regents University and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia, USA
| | - Hong Liu
- Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, PR China; Department of Cellular Biology and Anatomy, Georgia Regents University and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia, USA
| | - Jiefu Zhu
- Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, PR China; Department of Cellular Biology and Anatomy, Georgia Regents University and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia, USA
| | - Fuyou Liu
- Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, PR China; Department of Cellular Biology and Anatomy, Georgia Regents University and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia, USA
| | - Guochun Chen
- Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, PR China; Department of Cellular Biology and Anatomy, Georgia Regents University and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia, USA
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New developments in peritoneal fibroblast biology: implications for inflammation and fibrosis in peritoneal dialysis. BIOMED RESEARCH INTERNATIONAL 2015; 2015:134708. [PMID: 26495280 PMCID: PMC4606153 DOI: 10.1155/2015/134708] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Revised: 08/11/2015] [Accepted: 08/25/2015] [Indexed: 01/19/2023]
Abstract
Uraemia and long-term peritoneal dialysis (PD) can lead to fibrotic thickening of the peritoneal membrane, which may limit its dialytic function. Peritoneal fibrosis is associated with the appearance of myofibroblasts and expansion of extracellular matrix. The extent of contribution of resident peritoneal fibroblasts to these changes is a matter of debate. Recent studies point to a significant heterogeneity and complexity of the peritoneal fibroblast population. Here, we review recent developments in peritoneal fibroblast biology and summarize the current knowledge on the involvement of peritoneal fibroblasts in peritoneal inflammation and fibrosis.
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Vascular endothelial growth factor receptor-3 is a novel target to improve net ultrafiltration in methylglyoxal-induced peritoneal injury. J Transl Med 2015; 95:1029-43. [PMID: 26121315 DOI: 10.1038/labinvest.2015.87] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2014] [Revised: 04/30/2015] [Accepted: 05/18/2015] [Indexed: 01/31/2023] Open
Abstract
Appropriate fluid balance is important for good clinical outcomes and survival in patients on peritoneal dialysis. We recently reported that lymphangiogenesis associated with fibrosis developed in the peritoneal cavity via the transforming growth factor-β1-vascular endothelial growth factor-C (VEGF-C) pathway. We investigated whether VEGF receptor-3 (VEGFR-3), the receptor for VEGF-C and -D, might be a new target to improve net ultrafiltration by using adenovirus-expressing soluble VEGFR-3 (Adeno-sVEGFR-3) in rodent models of peritoneal injury induced by methylglyoxal (MGO). We demonstrated that lymphangiogenesis developed in these MGO models, especially in the diaphragm, indicating that lymphangiogenesis is a common feature in the peritoneal cavity with inflammation and fibrosis. In MGO models, VEGF-D was significantly increased in the diaphragm; however, VEGF-C was not significantly upregulated. Adeno-sVEGFR-3, which was detected on day 50 after administration via tail vein injections, successfully suppressed lymphangiogenesis in the diaphragm and parietal peritoneum in mouse MGO models without significant effects on fibrosis, inflammation, or neoangiogenesis. Drained volume in the peritoneal equilibration test using a 7.5% icodextrin peritoneal dialysis solution (the 7.5% icodextrin peritoneal equilibration test) was improved by Adeno-sVEGFR-3 on day 22 (P<0.05) and day 50 after reduction of inflammation (P<0.01), indicating that the 7.5% icodextrin peritoneal equilibration test identifies changes in lymphangiogenesis. The solute transport rate was not affected by suppression of lymphangiogenesis. In human peritoneal dialysis patients, the dialysate to plasma ratio of creatinine positively correlated with the dialysate VEGF-D concentration (P<0.001). VEGF-D mRNA was significantly higher in the peritoneal membranes of patients with ultrafiltration failure, indicating that VEGF-D is involved in the development of lymphangiogenesis in peritoneal dialysis patients. These results indicate that VEGFR-3 is a new target to improve net ultrafiltration by suppressing lymphatic absorption and that the 7.5% icodextrin peritoneal equilibration test is useful for estimation of lymphatic absorption.
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Takenaka T, Inoue T, Miyazaki T, Nishiyama A, Ishii N, Hayashi M, Suzuki H. Antialbuminuric actions of calcilytics in the remnant kidney. Am J Physiol Renal Physiol 2015; 309:F216-26. [PMID: 26017971 DOI: 10.1152/ajprenal.00003.2015] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Hyperphosphatemia accelerates the progression of chronic kidney diseases. In the present study, the effects of ronacaleret, a calcilytic agent, on renal injury were assessed in the following four groups of rats: 5/6-nephrectomized Wistar rats as a control (C group), rats treated with ronacaleret (3 mg·kg(-1)·day(-1); R group), rats treated with calcitriol (30 ng·kg(-1)·day(-1); V group), and rats treated with both ronacaleret and calcitriol (R + V group). Three months later, rats were euthanized under anesthesia, and the remnant kidneys were harvested for analysis. Albuminuria was lower in the R and V groups than in the C group (P < 0.05). Creatinine clearance was elevated in the R and V groups compared with the C group (P < 0.05). Serum Ca(2+) and renal ANG II were higher in the R + V group than in the C group (P < 0.05 for each), and serum phosphate was reduced in the R group compared with the C group (P < 0.05). Fibroblast growth factor-23 was lower in the R group and higher in the V and R + V groups than in the C group. However, parathyroid hormone did not differ significantly among the four groups. Renal klotho expression was elevated in the R and V groups compared with the C group (P < 0.05). The present data indicate that ronacaleret preserves klotho expression and renal function with reductions in serum phosphate and albuminuria in 5/6-nephrectomized rats. Our findings demonstrate that vitamin D prevents declines in klotho expression and renal function, suppressing albuminuria.
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Affiliation(s)
- Tsuneo Takenaka
- International University of Health and Welfare, Minato, Tokyo, Japan;
| | | | | | | | - Naohito Ishii
- Kitasato University, Sagamihara, Kanagawa, Japan; and
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Methylglyoxal Induced Basophilic Spindle Cells with Podoplanin at the Surface of Peritoneum in Rat Peritoneal Dialysis Model. BIOMED RESEARCH INTERNATIONAL 2015; 2015:289751. [PMID: 26064894 PMCID: PMC4433629 DOI: 10.1155/2015/289751] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2014] [Accepted: 12/16/2014] [Indexed: 11/18/2022]
Abstract
Peritoneal dialysis (PD) is a common treatment for patients with reduced or absent renal function. Long-term PD leads to peritoneal injury with structural changes and functional decline. At worst, peritoneal injury leads to encapsulating peritoneal sclerosis (EPS), which is a serious complication of PD. In order to carry out PD safely, it is important to define the mechanism of progression of peritoneal injury and EPS. We prepared rat models of peritoneal injury by intraperitoneal administration of glucose degradation products, such as methylglyoxal (MGO) or formaldehyde (FA), chlorhexidine gluconate (CG), and talc. In rats treated with MGO, peritoneal fibrous thickening with the appearance of basophilic spindle cells with podoplanin, cytokeratin, and α-smooth muscle actin at the surface of the peritoneum was observed. These cells may have been derived from mesothelial cells by epithelial-to-mesenchymal transition. In FA- or CG-treated rats, the peritoneum was thickened, and mesothelial cells were absent at the surface of the peritoneum. The CG- or MGO-treated rats presented with a so-called abdominal cocoon. In the talc-treated rats, extensive peritoneal adhesion and peritoneal thickening were observed. MGO-induced peritoneal injury model may reflect human histopathology and be suitable to analyze the mechanism of progression of peritoneal injury and EPS.
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Onishi A, Akimoto T, Morishita Y, Hirahara I, Inoue M, Kusano E, Nagata D. Peritoneal fibrosis induced by intraperitoneal methylglyoxal injection: the role of concurrent renal dysfunction. Am J Nephrol 2014; 40:381-90. [PMID: 25358632 DOI: 10.1159/000368424] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2014] [Accepted: 09/16/2014] [Indexed: 01/29/2023]
Abstract
BACKGROUND Peritoneal fibrosis (PF) is a serious pathophysiology of peritoneal dialysis (PD). An ongoing focus of research is the potential fibrogenic nature of methylglyoxal (MGO) in conventional PD fluid (PDF). The aim of the current study was to explore the effects of the uremic milieu on the promotion of PF by MGO using rats with adenine-induced renal failure (RF). METHODS Adenine-treated Sprague-Dawley rats were randomly assigned to receive continuous peritoneal injections of PDF with or without MGO for three weeks or were left untreated for the same duration. Rats without RF were also assigned to three groups. The peritoneal histology and expression levels of type I collagen, transforming growth factor-β1 (TGF-β1), α-smooth muscle actin (αSMA), Snail, matrix metalloproteinase-2 (MMP-2), advanced glycation end-products (AGEs) and the receptor for AGE (RAGE) were then analyzed. RESULTS Peritoneal treatment with 5 mM MGO accelerated the fibrous peritoneal thickening progression promoted by exposure to standard PDF in the rats with RF, but not in the rats with a normal renal function. Treatment with MGO significantly augmented the proliferation of mesenchymal-like mesothelial cells, accumulation of AGE, de novo expression of αSMA and RAGE and gene expression of type I collagen, TGF-β1, Snail and MMP-2, whereas both MGO and RF alone had, at most, marginal effects on the changes in these biological parameters. CONCLUSIONS In the present study, the adverse effects of MGO on the peritoneum became more prominent under conditions of a uremic milieu. These findings imply that MGO and uremia act cooperatively to induce PF.
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Affiliation(s)
- Akira Onishi
- Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Tochigi, Japan
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Kitamura M, Nishino T, Obata Y, Ozono Y, Koji T, Kohno S. New insights into therapeutic strategies for the treatment of peritoneal fibrosis: learning from histochemical analyses of animal models. Acta Histochem Cytochem 2014; 47:133-43. [PMID: 25392567 PMCID: PMC4164701 DOI: 10.1267/ahc.14025] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2014] [Accepted: 05/23/2014] [Indexed: 01/01/2023] Open
Abstract
Encapsulating peritoneal sclerosis (EPS) is a fatal complication that can occur in patients undergoing long-term peritoneal dialysis. It is characterized by bowel obstruction and marked sclerotic thickening of the peritoneal membrane. Although the mechanisms underlying the development of EPS are complex, angiogenesis, inflammation, and peritoneal fibrosis are known to be essential factors. Now, several animal models that exhibit EPS have pathophysiology similar to that of human EPS and have been proposed for use in research to provide insights into it. Recent histochemical methods also help us to understand the pathophysiology of EPS. Advances in basic research based on the findings in those animal models have enabled the development of several strategies for the prevention and treatment of EPS. We describe here interventional studies in some animal models for peritoneal fibrosis, one of the histological disorders findings characteristic to EPS, and we highlight the need for a sophisticated animal model that closely resembles human conditions.
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Affiliation(s)
- Mineaki Kitamura
- Second Department of Internal Medicine, Nagasaki University School of Medicine, 1–7–1 Sakamoto, Nagasaki, Japan
| | - Tomoya Nishino
- Second Department of Internal Medicine, Nagasaki University School of Medicine, 1–7–1 Sakamoto, Nagasaki, Japan
| | - Yoko Obata
- Second Department of Internal Medicine, Nagasaki University School of Medicine, 1–7–1 Sakamoto, Nagasaki, Japan
- Medical Education Development Center, Nagasaki University Hospital, 1–7–1 Sakamoto, Nagasaki, Japan
| | - Yoshiyuki Ozono
- Department of General Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1–7–1 Sakamoto, Nagasaki, Japan
| | - Takehiko Koji
- Department of Histology and Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, 1–12–4 Sakamoto, Nagasaki, Japan
| | - Shigeru Kohno
- Second Department of Internal Medicine, Nagasaki University School of Medicine, 1–7–1 Sakamoto, Nagasaki, Japan
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MiR-30b is involved in methylglyoxal-induced epithelial-mesenchymal transition of peritoneal mesothelial cells in rats. Cell Mol Biol Lett 2014; 19:315-29. [PMID: 24898602 PMCID: PMC6276001 DOI: 10.2478/s11658-014-0199-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2013] [Accepted: 05/25/2014] [Indexed: 12/18/2022] Open
Abstract
Epithelial-mesenchymal transition (EMT) of peritoneal mesothelial cells (PMC) is a major contributor to the pathogenesis of peritoneal fibrosis. EMT is at least in part caused by repeated exposure to glucose degradation products (GDPs), such as methylglyoxal (MGO). MiRNA contributes greatly to the EMT of PMCs. In this study, we tried to profile whether differences exist between the peritoneal membrane (PM) miRNA expression seen in control rats and that seen in rats injected intraperitoneally with MGO. We assessed whether miR-30b has a possible role in MGO-induced EMT of PMCs in rats. Comparative miRNA expression array and real-time PCR analyses were conducted for the control group at the start of the experiment and for the MGO group after 1 and 2 weeks. During the second week, the MGO rats were treated with: a chemically modified antisense RNA oligonucleotide (ASO) complementary to the mature miR-30b (ASO group); an miR-30b mismatch control sequence (MIS group); or a citrate buffer (EMT group). Bioinformatic analyses indicated that the 3′ untranslated region (3′-UTR) of bone morphogenetic protein 7 (BMP7) mRNA did contain a putative binding site for miR-30b. We also tried to investigate whether miR-30b targeted BMP7 in vitro by transfection. Of the upregulated miRNAs, miR-30b expression demonstrated the greatest increase. The administration of miR-30b ASO for two weeks significantly reduced α-SMA excretion and upregulated E-cadherin and BMP-7 expression. Our in vitro study showed that miR-30b directly targeted and inhibited BMP7 by binding to its 3’-UTR. Our results revealed that miR-30b is involved in MGO-induced EMT of PMCs in rats.
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Peritoneal fibrosis and the putative role of decorin. Int J Organ Transplant Med 2013. [DOI: 10.1016/j.hkjn.2013.09.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
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Yang CY, Chau YP, Lee HT, Kuo HY, Lee OK, Yang AH. Cannabinoid receptors as therapeutic targets for dialysis-induced peritoneal fibrosis. Am J Nephrol 2013; 37:50-8. [PMID: 23296044 DOI: 10.1159/000345726] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2012] [Accepted: 11/07/2012] [Indexed: 12/21/2022]
Abstract
BACKGROUND Long-term exposure to bioincompatible peritoneal dialysis solutions is frequently complicated with peritoneal fibrosis and ultrafiltration failure. As cannabinoid receptor (CBR) ligands have been reported to be beneficial to ameliorate the process of liver fibrosis, we strove to investigate their therapeutic potential to prevent peritoneal fibrosis. METHODS We used the rat model of peritoneal fibrosis induced by intraperitoneal injection of methylglyoxal and in vitro mesothelial cell culture to test the effects of CBR ligands, including the type 1 CBR (CB(1)R) antagonist and the type 2 CBR (CB(2)R) agonist. RESULTS In the methylglyoxal model, both intraperitoneal CB(1)R antagonist (AM281) and CB(2)R agonist (AM1241) treatment significantly ameliorated peritoneal fibrosis. In addition, CB(1)R antagonist was able to alleviate TGF-β(1)-induced dedifferentiation of mesothelial cells and to maintain epithelial integrity in vitro. CONCLUSIONS Intraperitoneal administration of CBR ligands (CB(1)R antagonist and CB(2)R agonist) offers a potential therapeutic strategy to reduce dialysis-induced peritoneal fibrosis and to prolong the peritoneal survival in peritoneal dialysis patients.
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Affiliation(s)
- Chih-Yu Yang
- Division of Nephrology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
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Yamamoto D, Takai S, Akimoto T, Hirahara I, Ito C, Muto S, Kusano E. Matrix metalloproteinase-2 inhibition by temocapril and its important role in peritoneal transport. Clin Exp Pharmacol Physiol 2012; 39:864-8. [PMID: 23013132 DOI: 10.1111/j.1440-1681.2012.12003.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
1. Matrix metalloproteinase (MMP)-2 plays an important role in tissue remodelling during peritoneal injury caused by peritoneal dialysis (PD), but MMP-2 inhibitors have not yet been used clinically. Recently, it was reported that captopril, an angiotensin-converting enzyme inhibitor (ACEI), can inhibit MMP-2. 2. To investigate the potential usefulness of ACEI during PD, the molecular interaction between the MMP-2 active site and the active form of temocapril (temocaprilat) was investigated using molecular modelling. Furthermore, the effects of temocapril on MMP-2 activity in peritoneal effluents and the peritoneal solute transport rate of PD patients were determined. 3. Temocaprilat bound to the MMP-2 active centre and recognized two hydrophobic substrate-binding sites in the MMP-2 molecular model. Matrix metalloproteinase-2 activity in peritoneal effluents was directly inhibited by temocaprilat (IC(50) 0.47 μmol/L). In one patient given temocapril, the peritoneal solute transport rate decreased gradually during PD. 4. Temocapril may prove to be an important candidate for development as a novel therapeutic agent for MMP-2 inhibition to prevent peritoneal injury caused by PD.
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Affiliation(s)
- Daisuke Yamamoto
- Biomedical Computation Center, Osaka Medical College, Osaka, Japan.
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Morinaga H, Sugiyama H, Inoue T, Takiue K, Kikumoto Y, Kitagawa M, Akagi S, Nakao K, Maeshima Y, Miyazaki I, Asanuma M, Hiramatsu M, Makino H. Effluent free radicals are associated with residual renal function and predict technique failure in peritoneal dialysis patients. Perit Dial Int 2012; 32:453-61. [PMID: 22215657 DOI: 10.3747/pdi.2011.00032] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
OBJECTIVE Residual renal function (RRF) is associated with low oxidative stress in peritoneal dialysis (PD). In the present study, we investigated the relationship between the impact of oxidative stress on RRF and patient outcomes during PD. METHODS Levels of free radicals (FRs) in effluent from the overnight dwell in 45 outpatients were determined by electron spin resonance spectrometry. The FR levels, clinical parameters, and the level of 8-hydroxy-2'-deoxyguanosine were evaluated at study start. The effects of effluent FR level on technique and patient survival were analyzed in a prospective cohort followed for 24 months. RESULTS Levels of effluent FRs showed significant negative correlations with daily urine volume and residual renal Kt/V, and positive correlations with plasma β(2)-microglobulin and effluent 8-hydroxy-2'-deoxyguanosine. A highly significant difference in technique survival (p < 0.05), but not patient survival, was observed for patients grouped by effluent FR quartile. The effluent FR level was independently associated with technique failure after adjusting for patient age, history of cardiovascular disease, and presence of diabetes mellitus (p < 0.001). The level of effluent FRs was associated with death-censored technique failure in both univariate (p < 0.001) and multivariate (p < 0.01) hazard models. Compared with patients remaining on PD, those withdrawn from the modality had significantly higher levels of effluent FRs (p < 0.005). CONCLUSIONS Elevated effluent FRs are associated with RRF and technique failure in stable PD patients. These findings highlight the importance of oxidative stress as an unfavorable prognostic factor in PD and emphasize that steps should be taken to minimize oxidative stress in these patients.
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Affiliation(s)
- Hiroshi Morinaga
- Department of Medicine and Clinical Science, Center for Chronic Kidney Disease and Peritoneal Dialysis, Okayama University Graduate School of Medicine, Okayama, Japan
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Epigallocatechin gallate suppresses peritoneal fibrosis in mice. Chem Biol Interact 2011; 195:95-104. [PMID: 22101032 DOI: 10.1016/j.cbi.2011.11.002] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2011] [Revised: 11/02/2011] [Accepted: 11/04/2011] [Indexed: 02/03/2023]
Abstract
Long-term peritoneal dialysis (PD) leads to histological changes in the peritoneal membrane. Angiogenesis and inflammation caused by glucose degradation products (GDPs) play crucial roles in peritoneal fibrosis. One such GDP is methylglyoxal (MGO), which enhances the formation of advanced glycation end products (AGEs). AGEs bind to their receptor (RAGE) and activate nuclear factor-κB (NF-κB), which is a key regulator of angiogenesis and inflammation. Recent studies have indicated that (-)-epigallocatechin gallate (EGCG), a tea polyphenol, inhibits angiogenesis and inflammation. Here, we examined whether EGCG suppresses peritoneal fibrosis in mice. Based on preliminary examination, 2mL of 40mM MGO or PD fluid was injected intraperitoneally and EGCG (50mg/kg) or saline was injected subcutaneously for 3weeks. In comparison to PD fluid+saline-treated mice, the peritoneal tissues of MGO+saline-treated mice showed marked thickening of the submesothelial compact zone. In the submesothelial compact zone of the MGO+saline-treated mice, CD31-positive vessels and vascular endothelial growth factor-positive cells were significantly increased, as were inflammation, F4/80-positive macrophages, and monocyte chemotactic protein-1. Moreover, 8-hydroxydeoxyguanosine, a marker of reactive oxygen species, and NF-κB, determined by Southwestern histochemistry, in the submesothelial compact zone were also increased in MGO+saline-treated mice. These changes were attenuated in MGO+EGCG-treated mice. We demonstrated that EGCG treatment suppresses peritoneal fibrosis via inhibition of NF-κB. Furthermore, EGCG inhibits reactive oxygen species production. The results of this study indicate that EGCG is a potentially novel candidate for the treatment of peritoneal fibrosis.
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Abstract
Encapsulating peritoneal sclerosis (EPS) is a rare complication of peritoneal dialysis (PD), but carries significant morbidity and mortality. We review the clinical features and radiologic and histologic changes found at diagnosis of EPS. Although EPS is strongly associated with the duration of PD, the pathogenesis remains only partly understood. We discuss the mechanisms thought to underlie the abnormally thickened, sclerotic peritoneal membrane seen in long-term PD patients including epithelial to mesenchymal transition and the molecular mediators of fibrosis and angiogenesis. We review how exposure to high-glucose, nonphysiological dialysis fluids, peritonitis, and uremia may be responsible for these changes. Much remains to be learned about optimal management of EPS, both medical and surgical, because the literature lacks controlled studies. Future research challenges include defining the role of surgery, immunosuppression, and antifibrotic agents in the management of EPS. We also need to understand why some patients progress from asymptomatic peritoneal sclerosis to the extreme levels of fibrin deposition and bowel encapsulation seen in EPS. Screening PD patients for potential future EPS remains difficult, and we need strategies for monitoring patients on longer-term PD that enable us to better quantify the risk of EPS for the individual patient.
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Affiliation(s)
- Catriona Goodlad
- Imperial College Kidney and Transplant Institute, Hammersmith Hospital, London, UK.
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Yamaguchi Y, Ishigaki T, Sano K, Miyamoto KI, Nomura S, Horiuchi T. Three-Dimensional Invasion of Epithelial–Mesenchymal Transition–Positive Human Peritoneal Mesothelial Cells into Collagen Gel is Promoted by the Concentration Gradient of Fibronectin. Perit Dial Int 2011; 31:477-85. [DOI: 10.3747/pdi.2010.00166] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Background In long-term peritoneal dialysis, myofibroblast-like cells found in the interstitium of the peritoneum are assumed to be a transformed type of mesothelial cell—epithelial-mesenchymal transition-positive [EMT(+)] human peritoneal mesothelial cells (HPMCs)—because they express a mesothelial marker, cytokeratin. However, no direct evidence about how these cells are able to invade from the mesothelium has yet been obtained. Aim In this study, we aimed to verify whether EMT(+) HPMCs would, in vitro, invade three-dimensionally along certain chemotactic factors. Methods We used reverse-transcriptase polymerase chain reaction to measure expression of Snail, E-cadherin, α5-integrin, and matrix metalloproteinase 2 (MMP2) messenger RNA (mRNA) in HPMCs exposed to 10 ng/mL transforming growth factor β1 (TGFβ1) and how that expression corresponds to cell motility, as represented by a video movie. We used the Transwell (12 μm pore diameter: Sigma-Aldrich, Tokyo, Japan) to construct a three-dimensional (3D) cell migration chamber. In the lower chamber, a concentration gradient of fibronectin (FN) or albumin(Alb) was formed in 0.1% type I collagen by diffusion ( C0 = 22 nmol/L; concentration gradient: C / C0 = 0.7). All cells beneath the membrane were counted 72 hours after 5x104 EMT(+) HPMCs (HPMCs after a 48-hour exposure to 10 ng/mL TGFβ1) had been spread in the upper chamber. Results After 72 hours, the increased motility of HPMCs resulting from their exposure to 10 ng/mL TGFβ1 had returned to baseline, but they retained an elongated morphology. Expression of Snail and MMP2 mRNA reached maximum at 24 hours. Expression of E-cadherin declined, and expression of α5-integrin increased continuously. In the 3D invasion study, significantly enhanced invasion by EMT(+) but not EMT(-) HPMCs was clearly seen in the presence of a FN concentration gradient ( p < 0.01), although invasion by EMT(+) and EMT(-) HPMCs in the absence of a FN concentration gradient was not statistically significantly different. Compared with the EMT(+) control (no concentration gradient), invasion by EMT(+) HPMCs was 2.1 ± 0.5 times (p < 0.05) and 1.4 ± 0.4 times (p = nonsignificant) higher along the FN and Alb concentration gradients respectively. Increased invasion along the FN concentration gradient was significantly inhibited (p < 0.05) when the HPMCs were pre-incubated with 5 μg/mL RGDS (a blocker for α5-integrin to FN). Conclusions We conclude that EMT(+) HPMCs invade collagen gel along the FN concentration gradient because of specific binding to RGDS receptors, which bind integrins such as α5-integrin, upregulating invasion-related gene expression associated with synthesis of the cytoskeleton protein α smooth muscle actin.
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Affiliation(s)
- Youhei Yamaguchi
- Division of Chemistry for Materials, Faculty of Engineering, Graduate School of Mie University, Tsu, Japan
| | - Tatsuya Ishigaki
- Division of Chemistry for Materials, Faculty of Engineering, Graduate School of Mie University, Tsu, Japan
| | - Koushi Sano
- Division of Chemistry for Materials, Faculty of Engineering, Graduate School of Mie University, Tsu, Japan
| | - Kei-Ichi Miyamoto
- Division of Chemistry for Materials, Faculty of Engineering, Graduate School of Mie University, Tsu, Japan
| | - Shinsuke Nomura
- Division of Therapeutic Blood Purification, Mie University School of Medicine, Tsu, Japan
| | - Takashi Horiuchi
- Division of Chemistry for Materials, Faculty of Engineering, Graduate School of Mie University, Tsu, Japan
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Perl J, Nessim SJ, Bargman JM. The biocompatibility of neutral pH, low-GDP peritoneal dialysis solutions: benefit at bench, bedside, or both? Kidney Int 2011; 79:814-24. [DOI: 10.1038/ki.2010.515] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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Kushiyama T, Oda T, Yamada M, Higashi K, Yamamoto K, Oshima N, Sakurai Y, Miura S, Kumagai H. Effects of liposome-encapsulated clodronate on chlorhexidine gluconate-induced peritoneal fibrosis in rats. Nephrol Dial Transplant 2011; 26:3143-54. [DOI: 10.1093/ndt/gfr068] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Hirahara I, Kusano E. Reply. Nephrol Dial Transplant 2011. [DOI: 10.1093/ndt/gfq700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Terawaki H, Nakao M, Nakayama K, Nakayama M, Kimura A, Takane K, Mitome J, Hamaguchi A, Ogura M, Yokoyama K, Ito S, Hosoya T. Peritoneal clearance and transport of methylglyoxal. Nephrol Dial Transplant 2010; 26:753-4; author reply 754-5. [PMID: 21097649 DOI: 10.1093/ndt/gfq698] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
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Hirahara I, Inoue M, Umino T, Saito O, Muto S, Kusano E. Matrix metalloproteinase levels in the drained dialysate reflect the peritoneal solute transport rate: a multicentre study in Japan. Nephrol Dial Transplant 2010; 26:1695-701. [PMID: 20921293 DOI: 10.1093/ndt/gfq593] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Long-term peritoneal dialysis (PD) leads to peritoneal injury with high solute transport of the peritoneal membrane. At worst, peritoneal injury leads to encapsulating peritoneal sclerosis with an extremely high mortality rate. To perform PD safely and adequately, it is necessary to monitor peritoneal injury. The aim of this study was to investigate the potential of matrix metalloproteinases (MMPs) as new indicators of peritoneal injury. METHODS The subjects included 215 PD patients with end-stage renal disease at 20 centres in Japan. MMPs or tissue inhibitors of MMP (TIMPs) in the drained dialysate were quantified with enzyme-linked immunosorbent assay. The peritoneal solute transport rate was assessed to estimate peritoneal injury and PD efficiency by the peritoneal equilibration test (PET). RESULTS MMP-2, MMP-3 and TIMP-1 levels in the drained dialysate obtained by the PET were correlated with the D/P Cr ratios (ρ = 0.69, ρ = 0.52, ρ = 0.55, respectively) and the D/D0 glucose ratios (ρ = -0.60, ρ = -0.47, ρ = -0.48, respectively). The measured D/S ratios of MMP-2 and TIMP-1 were significantly higher than the expected D/S ratios when MMP-2 and TIMP-1 would have been transported from only the circulation. The measured D/S ratios of MMP-3 nearly corresponded to the expected ratios. MMP-1 and TIMP-2 in the drainage were undetected in most patients. CONCLUSIONS From these results, most MMP-2 in the drained dialysate may be produced from the peritoneum, and MMP-2 is expected to be a useful marker of peritoneal injury or change in peritoneal solute transport.
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Affiliation(s)
- Ichiro Hirahara
- Division of Nephrology, Department of Internal Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.
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PPAR-γ agonist rosiglitazone protects peritoneal membrane from dialysis fluid-induced damage. J Transl Med 2010; 90:1517-32. [PMID: 20531289 DOI: 10.1038/labinvest.2010.111] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Exposure to non-physiological solutions during peritoneal dialysis (PD) produces structural alterations to the peritoneal membrane and ultrafiltration dysfunction. The high concentration of glucose and glucose degradation products in standard PD fluids induce a local diabetic environment, which leads to the formation of advanced glycation end products (AGEs) that have an important role in peritoneal membrane deterioration. Peroxisome proliferator-activated receptor γ (PPAR-γ) agonists are used to treat type II diabetes and they have beneficial effects on inflammation, fibrosis, and angiogenesis. Hence, we evaluated the efficacy of the PPAR-γ agonist rosiglitazone (RSG) in ameliorating peritoneal membrane damage in a mouse PD model, and we analyzed the mechanisms underlying the protection offered by RSG. Exposure of the peritoneum to PD fluid resulted in AGEs accumulation, an inflammatory response, the loss of mesothelial cell monolayer and invasion of the compact zone by mesothelial cells, fibrosis, angiogenesis, and functional impairment of the peritoneum. Administration of RSG diminished the accumulation of AGEs, preserved the mesothelial monolayer, decreased the number of invading mesothelial cells, reduced fibrosis and angiogenesis, and improved peritoneal function. Interestingly, instead of reducing the leukocyte recruitment, RSG administration enhanced this process and specifically, the recruitment of CD3+ lymphocytes. Furthermore, RSG treatment augmented the levels of the anti-inflammatory cytokine interleukin (IL)-10 and increased the recruitment of CD4+ CD25+ FoxP3+ cells, suggesting that regulatory T cells mediated the protection of the peritoneal membrane. In cell-culture experiments, RSG did not prevent or reverse the mesothelial to mesenchymal transition, although it decreased mesothelial cells apoptosis. Accordingly, RSG appears to produce pleiotropic protective effects on the peritoneal membrane by reducing the accumulation of AGEs and inflammation, and by preserving the mesothelial cells monolayer, highlighting the potential of PPAR-γ activation to ameliorate peritoneal deterioration in PD patients.
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Braun N, Alscher DM, Fritz P, Edenhofer I, Kimmel M, Gaspert A, Reimold F, Bode-Lesniewska B, Ziegler U, Biegger D, Wüthrich RP, Segerer S. Podoplanin-positive cells are a hallmark of encapsulating peritoneal sclerosis. Nephrol Dial Transplant 2010; 26:1033-41. [PMID: 20709739 DOI: 10.1093/ndt/gfq488] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Encapsulating peritoneal sclerosis (EPS) and simple peritoneal sclerosis are important complications of long-term peritoneal dialysis (PD). Podoplanin is expressed by mesothelial cells and lymphatic vessels, which are involved in inflammatory reactions in the peritoneal cavity. METHODS We studied 69 peritoneal biopsies from patients on PD (n = 16), patients with EPS (n = 18) and control biopsies taken at the time of hernia repair (n = 15) or appendectomy (n = 20). Immunohistochemistry was performed to localize podoplanin. Additionally, markers of endothelial cells, mesothelial cells, myofibroblasts (smooth muscle actin), proliferating cells, and double labelling for smooth muscle actin/podoplanin were used on selected biopsies. RESULTS Podoplanin was present on the endothelium of lymphatic vessels in the submesothelial fibrous tissue and on mesothelial cells. In patients on PD and in biopsies with appendicitis, the mesothelial cells demonstrated a cuboidal appearance and circumferential podoplanin staining, with gaps between the cells. The number of lymphatic vessels was variable, but prominent at sites of fibrosis. In patients with EPS, a diffuse infiltration of podoplanin-positive cells with a fibroblastic appearance was present in 15 out of 18 biopsies. This pattern was focally present in 3 out of 16 on PD and none in the 35 controls. The podoplanin-positive cells did not express the endothelial marker or the mesothelial marker (calretinin). CONCLUSIONS EPS is characterized by a population of podoplanin and smooth muscle actin double-positive cells. Podoplanin might be a suitable morphological marker supporting the diagnosis and might be involved in the pathogenesis of EPS.
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Affiliation(s)
- Niko Braun
- Department of Internal Medicine, Division of General Internal Medicine and Nephrology, Robert-Bosch-Hospital, Stuttgart, Germany
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Yamamoto D, Takai S, Hirahara I, Kusano E. Captopril directly inhibits matrix metalloproteinase-2 activity in continuous ambulatory peritoneal dialysis therapy. Clin Chim Acta 2010; 411:762-4. [DOI: 10.1016/j.cca.2010.02.059] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2009] [Revised: 01/08/2010] [Accepted: 02/17/2010] [Indexed: 11/16/2022]
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