|
1
|
Zhang Y, Shi S, Lin C, Zeng Q, Che L, Li Y, Lin W. Thiolutin, a novel NLRP3 inflammasome inhibitor, mitigates IgA nephropathy in mice. Int Immunopharmacol 2025; 152:114440. [PMID: 40086055 DOI: 10.1016/j.intimp.2025.114440] [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: 09/28/2024] [Revised: 02/26/2025] [Accepted: 03/04/2025] [Indexed: 03/16/2025]
Abstract
NLRP3 inflammasome plays a key role in IgA Nephropathy (IgAN) pathogenesis. Thiolutin (THL) is an NLRP3 inflammasome inhibitor with anti-inflammatory effects, but its role in IgAN is unclear. This study aimed to evaluate the protective efficacy of THL in IgAN mice, alongside assessing its inhibitory mechanisms. IgAN was induced by administration of bovine serum albumin combined with Staphylococcal Enterotoxin B in mice, followed by THL treatment. Kidney injury biomarkers, inflammatory cytokines, histological changes and the NLRP3 inflammasome pathway were assessed. The effect of THL on pyroptosis and action site on inflammasome was examined in J774A.1 cells, and co-immunoprecipitation was used to study specific protein interactions. In IgAN mice, THL treatment significantly reduced renal dysfunctional markers and histological injury without affecting hepatic function, accompanied by decreased serum IgA levels, renal IgA deposition and pro-inflammatory cytokine accumulation via regulating the mRNA and protein expression of key inflammasome components. It also attenuated pyroptosis and NLRP3 inflammasome activation instead of priming in macrophages, via disturbing the combination of NLRP3 with apoptosis-associated speck-like protein and NIMA-Related Kinase 7. THL has significant anti-inflammatory and renal protective effects in IgAN via inhibiting the NLRP3 inflammasome pathway. Its selective impact on the activation and assembly of the inflammasome, without affecting priming, highlights its potential as a targeted therapeutic agent in IgAN management.
Collapse
Affiliation(s)
- Yun Zhang
- Department of Renal Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, China
| | - Shuhan Shi
- Department of Renal Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, China
| | - Changda Lin
- Department of Renal Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, China
| | - Quanzuan Zeng
- Department of Renal Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, China
| | - Lishuang Che
- Department of Renal Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, China
| | - Yuangen Li
- Department of Renal Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, China
| | - Weiyuan Lin
- Department of Renal Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, China.
| |
Collapse
|
|
2
|
Jash R, Maji HS, Chowdhury A, Maparu K, Seksaria S, Gupta P, Paria A, Nandi A, Das A, Chattaraj B, Prasanth DNK. Oxymatrine ameliorates epithelial mesenchymal transition in IgA nephropathy induced rats. Tissue Cell 2025; 93:102671. [PMID: 39705868 DOI: 10.1016/j.tice.2024.102671] [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: 07/20/2024] [Revised: 12/04/2024] [Accepted: 12/06/2024] [Indexed: 12/23/2024]
Abstract
In this study, we investigated the efficacy of oxymatrine, a phytochemical alkaloid, in reducing inflammation and fibrosis in a rat model of IgA nephropathy (IgAN) through modulation of the TGF-β/SMAD signaling pathway. Thirty Sprague Dawley rats were randomized into control, IgAN, and treatment groups, the latter receiving oxymatrine postinduction of IgAN. Induced by bovine serum albumin, carbon tetrachloride, and lipopolysaccharides, the disease model was validated by immunofluorescence and histopathological analyses, confirming significant renal deposition of IgA and increased fibrosis markers (IL-6, TGF-β, SMAD 3, and α-SMA). Oxymatrine treatment led to a notable decrease in urine protein levels and red blood cells at 10 weeks, suggesting reduced kidney damage. There was no significant impact on the SGOT or SGPT levels, while it reduced the BUN, serum ALB and creatinine levels, indicating minimal hepatotoxicity and renoprotective effects. Histopathology demonstrated preservation of the glomerular diameter in the treatment group. Immunofluorescence and ELISA revealed a reduction in the levels of proinflammatory (IL-6,TNF-α) and profibrotic (TGF-β, SMAD 3, and α-SMA) markers in treated rats, suggesting that oxymatrine has renoprotective effects on the inhibition of pathological EMT processes and fibrosis in IgAN. Our results suggest that oxymatrine is a potential therapeutic agent for IgAN that attenuates disease progression by targeting the TGF-β/SMAD pathways involved in EMT and fibrosis. Further research is warranted to establish long-term efficacy and safety profiles.
Collapse
Affiliation(s)
- Rajiv Jash
- Department of Pharmaceutical Sciences, JIS University, Kolkata 700109, India; Department of Pharmacy, Sanaka Educational Trust's Group of Institutions, Malandighi, Durgapur, West Bengal 713212, India.
| | | | - Arnab Chowdhury
- Department of Pathology, Shri Ramkrishna Institute of Medical Sciences and Sanaka Hospital, Malandighi, Durgapur, West Bengal 713212, India
| | - Kousik Maparu
- Department of Pharmacy, Sanaka Educational Trust's Group of Institutions, Malandighi, Durgapur, West Bengal 713212, India
| | - Sanket Seksaria
- Department of Pharmacy, Sanaka Educational Trust's Group of Institutions, Malandighi, Durgapur, West Bengal 713212, India
| | - Priyanka Gupta
- Department of Pharmacy, Sanaka Educational Trust's Group of Institutions, Malandighi, Durgapur, West Bengal 713212, India
| | - Arghya Paria
- Department of Pharmacy, Sanaka Educational Trust's Group of Institutions, Malandighi, Durgapur, West Bengal 713212, India
| | - Arijit Nandi
- Department of Pharmacy, Sanaka Educational Trust's Group of Institutions, Malandighi, Durgapur, West Bengal 713212, India
| | - Anwesha Das
- Department of Pharmacy, Sanaka Educational Trust's Group of Institutions, Malandighi, Durgapur, West Bengal 713212, India
| | - Bornika Chattaraj
- Department of Pharmacy, Sanaka Educational Trust's Group of Institutions, Malandighi, Durgapur, West Bengal 713212, India
| | - Ds Nb K Prasanth
- School of Pharmacy & Technology Management, SVKM's Narsee Monjee Institute of Management Studies (NMIMS), Polepally SEZ, TSIIC, Jadcherla, Mahbubnagar, Hyderabad 509301, India
| |
Collapse
|
|
3
|
Gao ZX, Fang Y, Xu SZ, He YS, Ge M, Zhang P, Xu YQ, He T, Wang P, Wang DG, Pan HF. Integrated analysis of ATAC-seq and RNA-seq reveals the chromatin accessibility and transcriptional landscape of immunoglobulin a nephropathy. Clin Immunol 2025; 272:110432. [PMID: 39848509 DOI: 10.1016/j.clim.2025.110432] [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: 09/14/2024] [Revised: 01/17/2025] [Accepted: 01/18/2025] [Indexed: 01/25/2025]
Abstract
BACKGROUNDS The association between chromatin accessibility in CD4+ T cells and Immunoglobulin A nephropathy (IgAN) remains unclear. METHODS We performed the assay for transposase accessible chromatin with sequencing (ATAC-seq) and RNA sequencing (RNA-seq) on CD4+ T cells. ATAC-seq and RNA-seq were conducted to identify differentially accessible regions and differentially expressed genes (DEGs), respectively (P < 0.05, |log2 Fold Change| >1). QRT-PCR was utilized to validate target gene expression. RESULTS We identified 100,865 differentially accessible regions, of which 7225 exhibited higher accessibility in IgAN. Functional analysis revealed that these regions are enriched in T lymphocyte activation and immune pathways. ELF3, MEIS1, and NFYC were identified as key TFs associated with IgAN. QRT-PCR indicated a significant upregulation of hub genes including MEIS1 in IgAN. CONCLUSION We identified key TFs and genes by integrating ATAC-seq and RNA-seq, which provide novel therapeutic targets for IgAN and insights into its pathogenesis from an epigenetic perspective.
Collapse
Affiliation(s)
- Zhao-Xing Gao
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Center for Big Data and Population Health of IHM, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, 81 Meishan Road, Hefei, Anhui, China
| | - Yang Fang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Center for Big Data and Population Health of IHM, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, 81 Meishan Road, Hefei, Anhui, China
| | - Shu-Zhen Xu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Center for Big Data and Population Health of IHM, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, 81 Meishan Road, Hefei, Anhui, China
| | - Yi-Sheng He
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Center for Big Data and Population Health of IHM, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, 81 Meishan Road, Hefei, Anhui, China
| | - Man Ge
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Center for Big Data and Population Health of IHM, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, 81 Meishan Road, Hefei, Anhui, China
| | - Peng Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Center for Big Data and Population Health of IHM, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, 81 Meishan Road, Hefei, Anhui, China
| | - Yi-Qing Xu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Center for Big Data and Population Health of IHM, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, 81 Meishan Road, Hefei, Anhui, China
| | - Tian He
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Center for Big Data and Population Health of IHM, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, 81 Meishan Road, Hefei, Anhui, China
| | - Peng Wang
- Department of Health Promotion and Behavioral Sciences, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei 230032, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, 81 Meishan Road, Hefei, Anhui, China.
| | - De-Guang Wang
- Department of Nephrology, Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
| | - Hai-Feng Pan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Center for Big Data and Population Health of IHM, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, 81 Meishan Road, Hefei, Anhui, China.
| |
Collapse
|
|
4
|
Pang G, Ye L, Jiang Y, Wu Y, Zhang R, Yang H, Yang Y. Unveiling the bidirectional role of MMP9: A key player in kidney injury. Cell Signal 2024; 122:111312. [PMID: 39074714 DOI: 10.1016/j.cellsig.2024.111312] [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: 05/15/2024] [Revised: 07/04/2024] [Accepted: 07/22/2024] [Indexed: 07/31/2024]
Abstract
Matrix metalloproteinases (MMPs) are a group of zinc-dependent proteolytic metalloenzymes that are involved in numerous pathological conditions, including nephropathy. MMP9, a member of the MMPs family, is categorized as a constituent of the gelatinase B subgroup, and its involvement in extracellular matrix (ECM) remodeling and renal fibrosis highlights its importance in the development and progression of renal diseases. The exact role of MMP9 in the development of kidney diseases is still controversial. This study investigated the dual role of MMP9 in kidney injury, discussing its implications in the pathogenesis of kidney diseases and investigating the design and mechanism of MMP9 inhibitors based on previous studies. This study provides an effective basis for the development of novel and selective MMP9 inhibitors for treating renal diseases.
Collapse
Affiliation(s)
- Guiying Pang
- Anhui University of Traditional Chinese Medicine, Hefei 230000, People's Republic of China; Institute of Innovative Medicine, Biocytogen Pharmaceuticals (Beijing) Co, Ltd., Beijing 102609, People's Republic of China; Joint Graduate School, Yangtze Delta Drug Advanced Research Institute, Nantong 226133, People's Republic of China
| | - Ling Ye
- Anhui University of Traditional Chinese Medicine, Hefei 230000, People's Republic of China; Department of Pharmacology, Biocytogen Pharmaceuticals (Beijing) Co, Ltd, Beijing 102609, People's Republic of China; Joint Graduate School, Yangtze Delta Drug Advanced Research Institute, Nantong 226133, People's Republic of China
| | - Yinxiao Jiang
- Anhui University of Traditional Chinese Medicine, Hefei 230000, People's Republic of China; Joint Graduate School, Yangtze Delta Drug Advanced Research Institute, Nantong 226133, People's Republic of China
| | - Yilin Wu
- Anhui University of Traditional Chinese Medicine, Hefei 230000, People's Republic of China; Institute of Innovative Medicine, Biocytogen Pharmaceuticals (Beijing) Co, Ltd., Beijing 102609, People's Republic of China; Joint Graduate School, Yangtze Delta Drug Advanced Research Institute, Nantong 226133, People's Republic of China
| | - Rufeng Zhang
- Institute of Innovative Medicine, Biocytogen Pharmaceuticals (Beijing) Co, Ltd., Beijing 102609, People's Republic of China; Department of Pharmacology, Biocytogen Pharmaceuticals (Beijing) Co, Ltd, Beijing 102609, People's Republic of China
| | - Hongxu Yang
- Institute of Innovative Medicine, Biocytogen Pharmaceuticals (Beijing) Co, Ltd., Beijing 102609, People's Republic of China.
| | - Yi Yang
- Institute of Innovative Medicine, Biocytogen Pharmaceuticals (Beijing) Co, Ltd., Beijing 102609, People's Republic of China; Joint Graduate School, Yangtze Delta Drug Advanced Research Institute, Nantong 226133, People's Republic of China.
| |
Collapse
|
|
5
|
Lu KC, Tsai KW, Hu WC. Role of TGFβ-producing regulatory T cells in scleroderma and end-stage organ failure. Heliyon 2024; 10:e35590. [PMID: 39170360 PMCID: PMC11336735 DOI: 10.1016/j.heliyon.2024.e35590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 07/31/2024] [Accepted: 07/31/2024] [Indexed: 08/23/2024] Open
Abstract
Regulatory T cells (Tregs) are crucial immune cells that initiate a tolerable immune response. Transforming growth factor-beta (TGFβ) is a key cytokine produced by Tregs and plays a significant role in stimulating tissue fibrosis. Systemic sclerosis, an autoimmune disease characterized by organ fibrosis, is associated with an overrepresentation of regulatory T cells. This review aims to identify Treg-dominant tolerable host immune reactions and discuss their association with scleroderma and end-stage organ failure. End-stage organ failures, including heart failure, liver cirrhosis, uremia, and pulmonary fibrosis, are frequently linked to tissue fibrosis. This suggests that TGFβ-producing Tregs are involved in the pathogenesis of these conditions. However, the exact significance of TGFβ and the mechanisms through which it induces tolerable immune reactions during end-stage organ failure remain unclear. A deeper understanding of these mechanisms could lead to improved preventive and therapeutic strategies for these severe diseases.
Collapse
Affiliation(s)
- Kuo-Cheng Lu
- Division of Nephrology, Department of Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan
- Division of Nephrology, Department of Medicine, Fu Jen Catholic University Hospital, School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
| | - Kuo-Wang Tsai
- Department of Medical Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, 231, Taiwan
| | - Wan-Chung Hu
- Department of Medical Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, 231, Taiwan
- Department of Clinical Pathology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, 231, Taiwan
- Department of Biotechnology, Ming Chuan University, Taoyuan City, 333, Taiwan
| |
Collapse
|
|
6
|
Sun M, Shi G, Zhang X, Kan C, Xie S, Peng W, Liu W, Wang P, Zhang R. Deciphering roles of protein post-translational modifications in IgA nephropathy progression and potential therapy. Aging (Albany NY) 2024; 16:964-982. [PMID: 38175721 PMCID: PMC10817402 DOI: 10.18632/aging.205406] [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: 09/05/2023] [Accepted: 11/16/2023] [Indexed: 01/05/2024]
Abstract
Immunoglobulin A nephropathy (IgAN), one type of glomerulonephritis, displays the accumulation of glycosylated IgA in the mesangium. Studies have demonstrated that both genetics and epigenetics play a pivotal role in the occurrence and progression of IgAN. Post-translational modification (PTM) has been revealed to critically participate in IgAN development and progression because PTM dysregulation results in impaired degradation of proteins that regulate IgAN pathogenesis. A growing number of studies identify that PTMs, including sialylation, o-glycosylation, galactosylation, phosphorylation, ubiquitination and deubiquitination, modulate the initiation and progression of IgAN. Hence, in this review, we discuss the functions and mechanisms of PTMs in regulation of IgAN. Moreover, we outline numerous compounds that govern PTMs and attenuate IgAN progression. Targeting PTMs might be a useful strategy to ameliorate IgAN.
Collapse
Affiliation(s)
- Mengying Sun
- Department of Nephrology, Zhuhai People’s Hospital, Zhuhai Clinical Medical College of Jinan University, Zhuhai, Guangdong 519000, China
| | - Guojuan Shi
- Department of Nephrology, Zhuhai People’s Hospital, Zhuhai Clinical Medical College of Jinan University, Zhuhai, Guangdong 519000, China
| | - Xiaohan Zhang
- Department of Nephrology, Zhuhai People’s Hospital, Zhuhai Clinical Medical College of Jinan University, Zhuhai, Guangdong 519000, China
| | - Chao Kan
- Department of Nephrology, Zhuhai People’s Hospital, Zhuhai Clinical Medical College of Jinan University, Zhuhai, Guangdong 519000, China
| | - Shimin Xie
- Department of Nephrology, Zhuhai People’s Hospital, Zhuhai Clinical Medical College of Jinan University, Zhuhai, Guangdong 519000, China
| | - Weixiang Peng
- Department of Nephrology, Zhuhai People’s Hospital, Zhuhai Clinical Medical College of Jinan University, Zhuhai, Guangdong 519000, China
| | - Wenjun Liu
- Department of Medicine, Zhejiang Zhongwei Medical Research Center, Hangzhou, Zhejiang 310018, China
| | - Peter Wang
- Department of Medicine, Zhejiang Zhongwei Medical Research Center, Hangzhou, Zhejiang 310018, China
| | - Rui Zhang
- Department of Nephrology, Zhuhai People’s Hospital, Zhuhai Clinical Medical College of Jinan University, Zhuhai, Guangdong 519000, China
| |
Collapse
|
|
7
|
Zhang Y, Yang H, Jiang M, Nie X. Exploring the pathogenesis and treatment of IgA nephropathy based on epigenetics. Epigenomics 2023; 15:1017-1026. [PMID: 37909120 DOI: 10.2217/epi-2023-0318] [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] [Indexed: 11/02/2023] Open
Abstract
IgA nephropathy is the most common primary glomerulonephritis worldwide. However, its exact cause remains unclear, with known genetic factors explaining only 11% of the variation. Recently, researchers have turned their attention to epigenetic abnormalities in immune-related diseases, recognizing their significance in IgA nephropathy's development and progression. This emerging field has revolutionized our understanding of epigenetics in IgA nephropathy research. Though in its early stages, studying IgA nephropathy's epigenetics holds promise for unraveling its pathogenesis and identifying new biomarkers and therapies. This review aims to comprehensively analyze epigenetics' role in IgA nephropathy's development and suggest avenues for potential therapeutic interventions. In the future, assessing and modulating epigenetics may become integral in diagnosing, tailoring treatments and assessing prognoses for IgA nephropathy.
Collapse
Affiliation(s)
- Yunfan Zhang
- Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, 350025, China
- Department of Pediatrics, The 900th Hospital of Joint Logistic Support Force, PLA, Fuzhou, 350025, China
| | - Huanhuan Yang
- Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, 350025, China
- Department of Pediatrics, The 900th Hospital of Joint Logistic Support Force, PLA, Fuzhou, 350025, China
| | - Ming Jiang
- Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, 350025, China
- Department of Pediatrics, The 900th Hospital of Joint Logistic Support Force, PLA, Fuzhou, 350025, China
| | - Xiaojing Nie
- Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, 350025, China
- Department of Pediatrics, The 900th Hospital of Joint Logistic Support Force, PLA, Fuzhou, 350025, China
- Department of Pediatrics, Affiliated Dongfang Hospital, Xiamen University, Fuzhou, 350025, China
| |
Collapse
|
|
8
|
Bharti N, Agrawal V, Kamthan S, Prasad N, Agarwal V. Blood TGF-β1 and miRNA-21-5p levels predict renal fibrosis and outcome in IgA nephropathy. Int Urol Nephrol 2023; 55:1557-1564. [PMID: 36648741 PMCID: PMC9844190 DOI: 10.1007/s11255-023-03464-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Accepted: 01/10/2023] [Indexed: 01/18/2023]
Abstract
BACKGROUND IgA nephropathy (IgAN), the most common primary glomerulonephritis, often presents as advanced renal failure with end-stage renal disease at diagnosis. Tubulointerstitial injury and fibrosis on histology are the most important predictors of renal outcome. A non-invasive biomarker is required for assessment of progression in IgA nephropathy. We investigated the utility of blood profibrotic molecules, TGF-β1 and miRNA-21-5p (miR-21), to identify a non-invasive biomarker for renal fibrosis in IgAN. MATERIALS AND METHODS The study included 30 IgAN (mean age 31.5 ± 9 years) at the time of initial diagnosis, 25 age-sex-matched healthy controls and 10 Lupus nephritis patients as disease controls. Serum TGF-β1 was analyzed by enzyme-linked immunosorbent assay and plasma miR-21 by qRT-PCR, normalized with U6-snRNA. The levels were correlated with clinical features, laboratory parameters, histological Oxford MEST-C score and renal outcome. RESULTS The serum TGF-β1 and plasma miR-21 were significantly higher in patients with IgAN than in healthy controls. TGF-β1 significantly correlated with serum creatinine, eGFR, Oxford T score and miR-21. High plasma miR-21 was significantly associated with T score and interstitial inflammation. On multivariate analysis, high levels of TGF-β1 and miR-21 correlated with lower eGFR and T score, respectively. On a follow-up period of 21.5 months, high miR-21 expression at diagnosis was associated (p = 0.02) with a poor renal outcome having a shorter time to doubling of serum creatinine. CONCLUSION High blood TGF-β1 and miR-21 expression at diagnosis of IgAN show significant correlation with renal function and degree of chronic tubulointerstitial injury on histology.
Collapse
Affiliation(s)
- Niharika Bharti
- Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014, India
| | - Vinita Agrawal
- Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014, India.
| | - Shubhi Kamthan
- Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014, India
| | - Narayan Prasad
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014, India
| | - Vikas Agarwal
- Department of Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014, India
| |
Collapse
|
|
9
|
Chalkia A, Gakiopoulou H, Theohari I, Foukas PG, Vassilopoulos D, Petras D. Transforming Growth Factor-β1/Smad Signaling in Glomerulonephritis and Its Association with Progression to Chronic Kidney Disease. Am J Nephrol 2021; 52:653-665. [PMID: 34496361 DOI: 10.1159/000517619] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 06/02/2021] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Transforming growth factor-β1 (TGF-β1) is a multifunctional cytokine, with diverse roles in fibrosis and inflammation, which acts through Smad signaling in renal pathology. We intended to investigate the expression of TGF-β/Smad signaling in glomerulonephritis (GN) and to assess its role as risk factor for progression to chronic kidney disease (CKD). METHODS We evaluated the immunohistochemical expression of TGF-β1, phosphorylated Smad3 (pSmad3), and Smad7 semiquantitatively and quantitatively using computerized image analysis program in different compartments of 50 renal biopsies with GN, and the results were statistically analyzed with clinicopathological parameters. We also examined the associations among their expressions, the impact of their co-expression, and their role in progression to CKD. RESULTS TGF-β1 expression correlated positively with segmental glomerulosclerosis (p= 0.025) and creatinine level at diagnosis (p = 0.002), while pSmad3 expression with interstitial inflammation (p = 0.024). In glomerulus, concomitant expressions of high Smad7 and medium pSmad3 were observed to be correlated with renal inflammation, such as cellular crescent (p = 0.011), intense interstitial inflammation (p = 0.029), and lower serum complement (C) 3 (p = 0.028) and C4 (p = 0.029). We also reported a significant association between pSmad3 expression in glomerular endothelial cells of proliferative GN (p = 0.045) and in podocytes of nonproliferative GN (p = 0.005). Finally, on multivariate Cox-regression analysis, TGF-β1 expression (hazard ratio = 6.078; 95% confidence interval: 1.168-31.627; p = 0.032) was emerged as independent predictor for CKD. DISCUSSION/CONCLUSION TGF-β1/Smad signaling is upregulated with specific characteristics in different forms of GN. TGF-β1 expression is indicated as independent risk factor for progression to CKD, while specific co-expression pattern of pSmad3 and Smad7 in glomerulus is correlated with renal inflammation.
Collapse
Affiliation(s)
- Aglaia Chalkia
- Nephrology Department, Hippokration General Hospital, Athens, Greece
| | - Harikleia Gakiopoulou
- 1st Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Irini Theohari
- 1st Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Periklis G Foukas
- 2nd Department of Pathology, School of Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Dimitrios Vassilopoulos
- 2nd Department of Medicine and Laboratory, Clinical Immunology - Rheumatology Unit, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Dimitrios Petras
- Nephrology Department, Hippokration General Hospital, Athens, Greece
| |
Collapse
|
|
10
|
Jia NY, Liu XZ, Zhang Z, Zhang H. Weighted Gene Co-expression Network Analysis Reveals Different Immunity but Shared Renal Pathology Between IgA Nephropathy and Lupus Nephritis. Front Genet 2021; 12:634171. [PMID: 33854525 PMCID: PMC8039522 DOI: 10.3389/fgene.2021.634171] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 02/23/2021] [Indexed: 11/17/2022] Open
Abstract
Both IgA nephropathy (IgAN) and lupus nephritis (LN) are immunity-related diseases with a complex, polygenic, and pleiotropic genetic architecture. However, the mechanism by which the genetic variants impart immunity or renal dysfunction remains to be clarified. In this study, using gene expression datasets as a quantitative readout of peripheral blood mononuclear cell (PBMC)- and kidney-based molecular phenotypes, we analyzed the similarities and differences in the patterns of gene expression perturbations associated with the systematic and kidney immunity in IgAN and LN. Original gene expression datasets for PBMC, glomerulus, and tubule from IgAN and systemic lupus erythematosus (SLE) patients as well as corresponding controls were obtained from the Gene Expression Omnibus (GEO) database. The similarities and differences in the expression patterns were detected according to gene differential expression. Weighted gene co-expression network analysis (WGCNA) was used to cluster and screen the co-expressed gene modules. The disease correlations were then identified by cell-specific and functional enrichment analyses. By combining these results with the genotype data, we identified the differentially expressed genes causatively associated with the disease. There was a significant positive correlation with the kidney expression profile, but no significant correlation with PBMC. Three co-expression gene modules were screened by WGCNA and enrichment analysis. Among them, blue module was enriched for glomerulus and podocyte (P < 0.05) and positively correlated with both diseases (P < 0.05), mainly via immune regulatory pathways. Pink module and purple module were enriched for tubular epithelium and correlated with both diseases (P < 0.05) through predominant cell death and extracellular vesicle pathways, respectively. In genome-wide association study (GWAS) enrichment analysis, blue module was identified as the high-risk gene module that distinguishes LN from SLE and contains PSMB8 and PSMB9, the susceptibility genes for IgAN. In conclusion, IgAN and LN showed different systematic immunity but similarly abnormal immunity in kidney. Immunological pathways may be involved in the glomerulopathy and cell death together with the extracellular vesicle pathway, which may be involved in the tubular injury in both diseases. Blue module may cover the causal susceptibility gene for IgAN and LN.
Collapse
Affiliation(s)
- Ni-Ya Jia
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education of China, Beijing, China
| | - Xing-Zi Liu
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education of China, Beijing, China
| | - Zhao Zhang
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education of China, Beijing, China
| | - Hong Zhang
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education of China, Beijing, China
| |
Collapse
|
|
11
|
Pei S, Li Y. Huangkui Capsule in Combination with Leflunomide Improves Immunoglobulin A Nephropathy by Inhibiting the TGF-β1/Smad3 Signaling Pathway. Clinics (Sao Paulo) 2021; 76:e2904. [PMID: 34909911 PMCID: PMC8614623 DOI: 10.6061/clinics/2021/e2904] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 10/15/2021] [Indexed: 11/28/2022] Open
Abstract
OBJECTIVES To investigate the efficacy and potential molecular mechanism of Huangkui capsule in combination with leflunomide (HKL) for the treatment of immunoglobulin A nephropathy (IgAN). METHODS IgAN rat models were constructed by treating rats with bovine serum albumin, lipopolysaccharide, and tetrachloromethane. Th22 cells were isolated from the blood samples of patients with IgAN using a CD4+ T cell isolation kit. The expression levels of the components of the TGF-β1/Smad3 signaling pathway, namely, TGF-β1, Smad2, Smad3, Smad4, and Smad7, were detected using quantitative reverse transcription polymerase chain reaction. Cell proliferation was determined using the MTT assay, cell viability was determined using the WST 1 method, and the chemotaxis of Th22 cells was observed using the wound healing assay. Changes in the histology of the kidney tissues were analyzed using hematoxylin and eosin staining. RESULTS Compared with IgAN rats, the rats subjected to HKL treatment showed good improvement in kidney injuries, and the combined drug treatment performed much better than the single-drug treatment. In addition, following HKL treatment, the viability, proliferation, and chemotaxis of Th22 cells dramatically decreased (*p<0.05, **p<0.01, and ***p<0.001). In addition, CCL20, CCL22, and CCL27 levels decreased and the expression of the key components of the TGF-β1/Smad3 signaling pathway was downregulated in IgAN rats and Th22 cells (*p<0.05, ***p<0.001). CONCLUSIONS By targeting the TGF-β1/Smad3 signaling pathway, HKL treatment can improve kidney injury in IgAN rats as well as the excessive proliferation and metastasis of Th22 cells.
Collapse
Affiliation(s)
- Shuwen Pei
- Department of Nephrology, Harbin First Hospital, Harbin, Heilongjiang 15000, China
- Corresponding author. E-mail:
| | - Yan Li
- Intensive Care Unit, Harbin First Hospital, Harbin, Heilongjiang 15000, China
| |
Collapse
|
|
12
|
Maeda Y, Takasawa K, Ishii T, Nagashima A, Mouri M, Kunieda J, Morisaki H, Ito T, Mori M, Kashimada K, Doi S, Morio T. A Nonsense SMAD3 Mutation in a Girl with Familial Thoracic Aortic Aneurysm and Dissection without Joint Abnormality. Cardiology 2019; 144:53-59. [PMID: 31587008 DOI: 10.1159/000502972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 08/27/2019] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Thoracic aortic aneurysms and dissections (TAAD) are rare in children and often associated with underlying genetic disorders accompanied with other systemic manifestations, including connective or osteo-articular tissue diseases. CASE PRESENTATION We report the case of a 10-year-old girl with a novel nonsense SMAD3 mutation, p.Glu102X, who presented with familial TAAD without any signs of osteoarthritis. Histological analysis of aorta fragments from the patient with TAAD obtained during surgery revealed elastin degradation and inflammatory infiltration of T cells with dense CD31 + microvessels, which is consistent with previous findings. Interestingly, the family members with the SMAD3 mutation developed IgA nephropathy. CONCLUSION Because the TGF-β/Smad signalling pathway plays an important role in the primary pathogenesis of IgA nephropathy and TAAD, we presume that IgA nephropathy could be a novel clinical phenotype of SMAD3 deficiency. Further accumulation of genetically proven cases with SMAD3 deficiency is needed to more accurately characterize phenotypic variability and elucidate a wide spectrum of TGF-β-associated disorders.
Collapse
Affiliation(s)
- Yoshichika Maeda
- Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kei Takasawa
- Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan,
| | - Taku Ishii
- Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Ayako Nagashima
- Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Mariko Mouri
- Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.,Department of Lifetime Clinical Immunology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Junko Kunieda
- Department of Comprehensive Pathology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hiroko Morisaki
- Department of Medical Genetics, Sakakibara Heart Institute, Tokyo, Japan
| | - Takashi Ito
- Department of Human Pathology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Masaaki Mori
- Department of Lifetime Clinical Immunology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kenichi Kashimada
- Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shozaburo Doi
- Department of Pediatrics, Perinatal and Maternal Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tomohiro Morio
- Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan
| |
Collapse
|
|
13
|
Wang S, Zhang K, Hu JL, Wu WC, Liu X, Ge N, Guo JT, Wang GX, Sun SY. Endoscopic resection of the pancreatic tail and subsequent wound healing mechanisms in a porcine model. World J Gastroenterol 2019; 25:2623-2635. [PMID: 31210714 PMCID: PMC6558443 DOI: 10.3748/wjg.v25.i21.2623] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 05/06/2019] [Accepted: 05/08/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Laparoscopic resection of the pancreatic body and tail is the predominant methodology to remove lesions in these locations; its safety and surgical planning are relatively mature, but it remains a complex and high-precision surgical operation, requiring abundant experience and skills in laparoscopic surgery, with a 10% rate of complications. AIM To verify the feasibility and safety, as well as to examine the complications of endoscopic pancreatectomy and healing mechanisms of pancreatic wounds after endoscopic resection. METHODS Transgastric endoscopic resections of varying sizes of pancreases were performed in 15 healthy Bama miniature pigs. The technical success rate, the incidence of serious complications, and the survival of the animals were studied. The healing of the wounds was evaluated by sacrificing the animals at various time points. Finally, the expression of transforming growth factor-β1 and Smad3/Smad7 in the surgical site was examined by immunohistochemistry to explore the role of these factors in wound healing of the pancreas. RESULTS Partial and total resections were successfully performed in two groups of animals, respectively. The technical success rate and the survival rate of the pigs were both 100%. We obtained 12 pancreatic tissue samples by endoscopic resection. The pancreatic wounds were closed with metal clips in one group and the wounds healed well by forming scars. There was a small amount of pancreatic leakage in the other group, but it can be fully encapsulated. The level of transforming growth factor-β1 (TGF-β1) in the wounds increased during the inflammatory and fibrous hyperplasia phases, and decreased in the scar phase. The expression of Smad3 paralleled that of TGF-β1, while the expression of Smad7 had an inverse relationship with the expression of TGF-β1. CONCLUSION Purely transgastric endoscopic resection of the pancreas is a safe, effective, and feasible procedure, but the incidence of pancreatic leakage in total pancreatic tail resection is high. The expression of TGF-β1 and Smad3/Samd7 is related to the progression of pancreatic wound healing.
Collapse
Affiliation(s)
- Sheng Wang
- Endoscopy Center, Shengjing Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Kai Zhang
- Endoscopy Center, Shengjing Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Jin-Long Hu
- Endoscopy Center, Shengjing Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Wei-Chao Wu
- Endoscopy Center, Shengjing Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Xiang Liu
- Endoscopy Center, Shengjing Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Nan Ge
- Endoscopy Center, Shengjing Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Jin-Tao Guo
- Endoscopy Center, Shengjing Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Guo-Xin Wang
- Endoscopy Center, Shengjing Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Si-Yu Sun
- Endoscopy Center, Shengjing Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| |
Collapse
|
|
14
|
Jie L, Pengcheng Q, Qiaoyan H, Linlin B, Meng Z, Fang W, Min J, Li Y, Ya Z, Qian Y, Siwang W. Dencichine ameliorates kidney injury in induced type II diabetic nephropathy via the TGF-β/Smad signalling pathway. Eur J Pharmacol 2017. [PMID: 28633927 DOI: 10.1016/j.ejphar.2017.06.024] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Diabetic nephropathy (DN), a common complication associated with both type I and type II diabetes mellitus (DM), is a major cause of chronic nephropathy and a common cause of end-stage renal diseases (ESRD) throughout the world. This study is aimed to determine whether dencichine (De) can ameliorate renal damage in high-glucose-and-fat diet combined STZ (streptozocin) induced DN in type II DM rats and to investigate the potential underlying mechanisms. Markers of metabolism, diabetes, and renal function, and levels of extracellular matrix (ECM) collagen I (Col I), collagen IV (Col IV), fibronectin (FN) and laminin (LN), and of proteins in the TGF-β/Smad pathway were analysed through RT-PCR, western blot, immunofluorescence and immunohistochemistry. The results show that De significantly alleviates metabolism disorder, improved renal function, relieved pathological alterations in the glomerulus of DN rats, decreased ECM deposition and increased the ratio of matrix metalloproteinase (MMP)-9 to tissue inhibitor of metalloproteinase (TIMP)-1 both in vivo and in vitro. Moreover, De negatively regulated TGF-β/Smad signalling pathway and increased the expression of Smad7, an endogenic inhibitory Smad located downstream of the signalling pathway. In conclusion, we provide experimental evidence indicating that the renoprotective effect of De could significantly prevent the progression of DN possibly attribute to down-regulation of the TGF-β/Smad pathway and rebalance the deposition and degradation of ECM proteins.
Collapse
Affiliation(s)
- Li Jie
- Department of Natural Medicine, Fourth Military Medical University, 710032 Xi'an, China
| | - Qiu Pengcheng
- Department of Natural Medicine, Fourth Military Medical University, 710032 Xi'an, China
| | - He Qiaoyan
- Department of Natural Medicine, Fourth Military Medical University, 710032 Xi'an, China
| | - Bi Linlin
- Department of Natural Medicine, Fourth Military Medical University, 710032 Xi'an, China
| | - Zhang Meng
- Department of Natural Medicine, Fourth Military Medical University, 710032 Xi'an, China
| | - Wang Fang
- Department of Natural Medicine, Fourth Military Medical University, 710032 Xi'an, China
| | - Jia Min
- Department of Natural Medicine, Fourth Military Medical University, 710032 Xi'an, China; Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Institute of Basic and Translational Medicine, Xi'an Medical University, 710021 Xi'an, China
| | - Yan Li
- Department of Natural Medicine, Fourth Military Medical University, 710032 Xi'an, China
| | - Zhang Ya
- Department of Natural Medicine, Fourth Military Medical University, 710032 Xi'an, China
| | - Yang Qian
- Department of Natural Medicine, Fourth Military Medical University, 710032 Xi'an, China
| | - Wang Siwang
- Department of Natural Medicine, Fourth Military Medical University, 710032 Xi'an, China.
| |
Collapse
|
|
15
|
Xu H, Li P, Liu M, Liu C, Sun Z, Guo X, Zhang Y. CCN2 and CCN5 exerts opposing effect on fibroblast proliferation and transdifferentiation induced by TGF-β. Clin Exp Pharmacol Physiol 2016. [PMID: 26218313 DOI: 10.1111/1440-1681.12470] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Epidural fibrosis might occur after lumbar discectomy and contributes to failed back syndrome. Transforming growth factor (TGF)-β has been reported to influence multiple organ fibrosis, in which connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed 2 (CCN2) and CCN5 are involved. However, the effect of CCN2 and CCN5 on TGF-β induced fibrosis has not yet been elucidated. This study reports that CCN2 and CCN5 play opposing roles in cell proliferation and transdifferentiation of human skin fibroblasts or rabbit epidural scar-derived fibroblasts exposed to TGF-β. We observed that TGF-β1 induced fibroblasts proliferation and differentiation in a dose-dependent manner (from 0 μg/L to 20 μg/L). Meanwhile, CCN2 expression is up-regulated while CCN5 expression is inhibited by TGF-β1 exposure. Furthermore, it is demonstrated that CCN2 overexpression leads to promoted proliferation and elevated collagen and α-smooth muscle actin (α-SMA) expression, which are inhibited by CCN5 overexpression. Moreover, it is shown that the cysteine knot (CT) domain, present in CCN2 but absent in CCN5, plays an essential part in fibroblast proliferation and differentiation. Additionally, enhanced TGF-β and CCN2 expression but decreased CCN5 expression is found in rabbit epidural scar-derived fibroblasts. Overall, the results show the opposing effects of CCN2 and CCN5 on fibroblast proliferation and transdifferentiation induced by TGF-β.
Collapse
Affiliation(s)
- Honghai Xu
- Department of Orthopaedics, Third Affiliated Hospital (Shaanxi Provincial People's Hospital), Xi'an, Shaanxi, China
| | - Peng Li
- Xi 'an Medical College, Xi'an, Shaanxi, China
| | | | - Cong Liu
- Xi 'an Medical College, Xi'an, Shaanxi, China
| | - Zhengming Sun
- Department of Orthopaedics, Third Affiliated Hospital (Shaanxi Provincial People's Hospital), Xi'an, Shaanxi, China
| | - Xiong Guo
- Department of the Faculty of Public Health, Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Yuelin Zhang
- Department of Neurosurgery, Third Affiliated Hospital (Shaanxi Provincial People's Hospital), Xi'an, Shaanxi, China
| |
Collapse
|
|
16
|
Zhang C, Zeng X, Li Z, Wang Z, Li S. Immunoglobulin A nephropathy: current progress and future directions. Transl Res 2015; 166:134-44. [PMID: 25797891 DOI: 10.1016/j.trsl.2015.02.007] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2014] [Revised: 02/25/2015] [Accepted: 02/26/2015] [Indexed: 01/10/2023]
Abstract
Immunoglobulin A (IgA) nephropathy is the most prevalent form of primary glomerulonephritis that often leads to end-stage kidney failure, thereby representing a major health challenge worldwide. Tremendous effort has been dedicated to the diagnosis, monitoring, and treatment of the disease, and the past several years have witnessed exciting advances that have enriched our understanding of the biology, etiology, and pathology of IgA nephropathy. The disease is characterized by predominant deposition of IgA immune complexes that progressively causes activation of mesangial cells, glomerular inflammation, and ultimately renal injury. Multiple recent independent high-throughput studies in cohorts have identified key susceptibility alleles, such as the major histocompatibility complex loci that are significantly associated with the risk of disease occurrence. Notably, a fraction of these risk loci encode proteins that participate in immune defense against mucosal pathogens, particularly intestinal nematodes, indicating a linkage between IgA-mediated antihelminth immunity and the pathogenesis of IgA nephropathy. The emerging "omics" technology also allows for systemic analysis of urinary and serum samples as a noninvasive procedure for diagnosis and prognosis, as demonstrated by several studies implicating the proteomic signature and microRNA profile as promising diagnostic and prognostic parameters. In the clinic, the current treatment protocol relies on suppression of the renin-angiotensin system to control blood pressure and proteinuria. This review scrutinizes and summarizes recent relevant findings that aim to translate researchers' benchside knowledge of disease initiation and development into patients' bedside diagnosis and therapy.
Collapse
Affiliation(s)
- Chunlei Zhang
- Laboratory of Science Department, Shenzhen Affiliated Hospital, Guangzhou University of Traditional Chinese Medicine, Shenzhen, China
| | - Xuehui Zeng
- Laboratory of Science Department, Shenzhen Affiliated Hospital, Guangzhou University of Traditional Chinese Medicine, Shenzhen, China
| | - Zhongxin Li
- Laboratory of Science Department, Shenzhen Affiliated Hospital, Guangzhou University of Traditional Chinese Medicine, Shenzhen, China
| | - Zhe Wang
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Tex
| | - Shunmin Li
- Department of Nephrology, Shenzhen Affiliated Hospital, Guangzhou University of Traditional Chinese Medicine, Shenzhen, China.
| |
Collapse
|
|
17
|
Topaloglu R, Orhan D, Bilginer Y, Karabulut E, Ozaltin F, Duzova A, Kale G, Besbas N. Clinicopathological and immunohistological features in childhood IgA nephropathy: a single-centre experience. Clin Kidney J 2013; 6:169-175. [PMID: 24175085 PMCID: PMC3811980 DOI: 10.1093/ckj/sft004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2012] [Accepted: 01/07/2013] [Indexed: 01/14/2023] Open
Abstract
Background IgA nephropathy is a glomerular disease diagnosed by renal biopsy and is characterized by a highly variable course ranging from a completely benign condition to rapidly progressive renal failure. We aimed to evaluate the clinical, histopathological and inflammatory characteristics of children with IgA nephropathy. Methods Data of 37 patients with IgA nephropathy diagnosed between the years 1980 and 2008 were retrospectively reviewed. Immunohistochemistry was performed in 24 patients. Expression of CD3, CD4, CD8, CD20, CD68, IL-1β, IL-10, IL-17, TGF-β, TNF-α and the newly proposed tubulointerstitial fibrosis marker nestin were evaluated. Results The median age at diagnosis was 10 years. Recurrent macroscopic haematuria (66%) was the most common clinical manifestation, and 35% of the patients had synpharyngitic presentation. A significant correlation was found between proteinuria and increase in mesangial matrix (r = 0.406, P = 0.013). The presence of CD4+ T lymphocytes and CD68+ macrophages were also significantly associated with proteinuria >1 g/day. While cytokines IL-1β, IL-10 and TNF-α were mainly expressed in tubular epithelial cells, TGF-β was evident in glomeruli but they had no correlation to clinical features and severity of the disease. Nestin was detected at the tubules in almost half of the patients with no correlation to proteinuria and tubulointersititial fibrosis. Conclusions We found a correlation between proteinuria and mesangial matrix expansion. The presence of CD4+ T-lymphocytes and CD68+ macrophages were also significantly associated with proteinuria >1 g/day. Although there are many evidences, for immunological basis of IgA nephropathy, the immunological markers were not fully expressed in children to evaluate glomerular and tubulointerstitial inflammation, and progression of the disease. Further studies with the extended number of children are needed to shed light on the immunological basis of the disease.
Collapse
Affiliation(s)
- Rezan Topaloglu
- Department of Pediatric Nephrology and Rheumatology , Faculty of Medicine, Hacettepe University , Ankara , Turkey
| | | | | | | | | | | | | | | |
Collapse
|
|
18
|
Wang G, Kwan BCH, Lai FMM, Chow KM, Li PKT, Szeto CC. Urinary miR-21, miR-29, and miR-93: novel biomarkers of fibrosis. Am J Nephrol 2012; 36:412-8. [PMID: 23108026 DOI: 10.1159/000343452] [Citation(s) in RCA: 121] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2012] [Accepted: 09/12/2012] [Indexed: 01/22/2023]
Abstract
BACKGROUND MicroRNAs (miRNAs) play important roles in the progression of renal fibrosis. We studied the urinary levels of miR-21, miR-29 family and miR-93, which are downstream mediators of the transforming growth factor-β(1) (TGF-β(1)), in patients with immunoglobulin A (IgA) nephropathy. METHODS We studied the urinary miRNA levels of 43 IgA nephropathy patients and 13 healthy controls. RESULTS The IgA nephropathy group had significantly lower urinary miR-29b and miR-29c, but higher miR-93 levels than controls. Proteinuria significantly correlated with urinary levels of miR-29b (r = -0.388, p = 0.003) and miR-29c (r = -0.409, p = 0.002). Glomerular filtration rate significantly correlated with urinary levels of miR-21 (r = 0.338, p = 0.028), miR-29b (r = 0.333, p = 0.031) and miR-29c (r = 0.304, p = 0.050). Urinary miR-93 level significantly correlated with glomerular scarring (r = -0.392, p = 0.010). Urinary miRNA level of SMAD3, but not TGF-β(1), correlated with urinary miR-21 (r = 0.624, p < 0.001), miR-29b (r = 0.566, p < 0.001), miR-29c (r = 0.619, p < 0.001) and miR-93 (r = 0.332, p = 0.032). CONCLUSIONS Urinary miR-29b and miR-29c levels correlated with proteinuria and renal function, while urinary miR-93 level correlated with glomerular scarring. More importantly, urinary levels of these miRNA targets significantly correlated with urinary SMAD3 level. Our results suggest that these miRNA targets are regulated by the TGF-β(1)/SMAD3 pathway and they may play important roles in the development of progressive renal fibrosis in IgA nephropathy.
Collapse
Affiliation(s)
- Gang Wang
- Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, SAR, China
| | | | | | | | | | | |
Collapse
|
|
19
|
Deng YL, Xiong XZ, Cheng NS. Organ fibrosis inhibited by blocking transforming growth factor-β signaling via peroxisome proliferator-activated receptor γ agonists. Hepatobiliary Pancreat Dis Int 2012; 11:467-78. [PMID: 23060391 DOI: 10.1016/s1499-3872(12)60210-0] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Organ fibrosis has been viewed as one of the major medical problems, which can lead to progressive dysfunction of the liver, lung, kidney, skin, heart, and eventually death of patients. Fibrosis is initiated by a variety of pathological, physiological, biochemical, and physical factors. Regardless of their different etiologies, they all share a common pathogenetic process: excessive activation of the key profibrotic cytokine, transforming growth factor-beta (TGF-beta). Peroxisome proliferator-activated receptor gamma (PPARgamma), a ligand-activated transcription factor of the nuclear receptor superfamily, has received particular attention in recent years, because the activation of PPARgamma by both natural and synthetic agonists could effectively inhibit TGF-beta-induced profibrotic effects in many organs. DATA SOURCES The English-language medical databases, PubMed, Elsevier and SpringerLink were searched for articles on PPARgamma, TGF-beta, and fibrosis, and related topics. RESULTS TGF-beta is recognized as a key profibrotic cytokine. Excessive activation of TGF-beta increases synthesis of extracellular matrix proteins and decreases their degradation, associated with a gradual destruction of normal tissue architecture and function, whereas PPARgamma agonists inhibit TGF-beta signal transduction and are effective antifibrogenic agents in many organs including the liver, lung, kidney, skin and heart. CONCLUSIONS The main antifibrotic activity of PPARgamma agonists is to suppress the TGF-beta signaling pathway by so-called PPARgamma-dependent effect. In addition, PPARgamma agonists, especially 15d-PGJ2, also exert potentially antifibrotic activity independent of PPARgamma activation. TGF-beta1/Smads signaling not only plays many essential roles in multiple developmental processes, but also forms cross-talk networks with other signal pathways, and their inhibition by PPARgamma agonists certainly affects the cytokine networks and causes non-suspected side-effects. Anti-TGF-beta therapies with PPARgamma agonists may have to be carefully tailored to be tissue- and target gene-specific to minimize side-effects, indicating a great challenge to the medical research at present.
Collapse
Affiliation(s)
- Yi-Lei Deng
- Department of General Surgery, West China Hospital, Sichuan University, Chengdu 610041, China
| | | | | |
Collapse
|