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Lee MJ, Yim H, Park JE, Park I, Kim H, Shin GT. Urinary GADD45G Protein Excretion Is Associated with IgA Nephropathy Progression. Biomedicines 2024; 12:2846. [PMID: 39767752 PMCID: PMC11673765 DOI: 10.3390/biomedicines12122846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 12/09/2024] [Accepted: 12/11/2024] [Indexed: 01/11/2025] Open
Abstract
Background: Growth arrest and DNA damage 45G (GADD45G) is a family of proteins involved in DNA damage response and cell growth arrest. In this study, we show evidence that urinary GADD45G protein is associated with the progression of IgA nephropathy. Methods: Patients diagnosed with IgA nephropathy without reversible acute kidney injury at study initiation and with at least one subsequent serum creatinine (SCr) measurement were included. A 50% or greater increase in SCr level was used as an endpoint for the deterioration of renal function. Enzyme-linked immunosorbent assay (ELISA) was performed using a Human GADD45G ELISA kit. Renal biopsy tissues were stained with a monoclonal mouse anti-GADD45G antibody. Results: Forty-five patients whose renal biopsy revealed IgA nephropathy were enrolled. Urinary GADD45G and urinary protein concentrations were 1.26 [0.69-2.20] μg/g creatinine and 0.65 [0.24-1.60] g/g creatinine, respectively. Urinary GADD45G showed significant positive correlations with SCr-slopes and urinary protein. The SCr-slope of the highest tertile group of urinary GADD45G (above 1.95 μg/g creatinine) was significantly higher than that of the lowest tertile group (below 0.90 μg/g). Univariate Cox regression analysis showed that urinary GADD45G was significantly associated with deterioration of renal function. A Kaplan-Meier test showed a significant difference in event-free survival for deterioration of renal function between the highest urinary GADD45G tertile group and other tertile groups. The area under the receiver operating characteristics (ROC) curve indicated urinary GADD45G had a good performance in predicting renal outcome (cut-off point 1.67 μg/g, positive predictive value 36.8%, negative predictive value 100%). Immunohistochemistry showed that GADD45G was expressed across all pathologic grades of IgA nephropathy and mainly detected in the cytoplasm of renal tubules, whereas no staining was noted in normal tissues. Conclusions: Urinary GADD45G excretion was significantly associated with kidney disease progression in patients with IgA nephropathy.
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Affiliation(s)
- Min-Jeong Lee
- Department of Nephrology, Ajou University School of Medicine, Suwon 16499, Republic of Korea; (M.-J.L.); (J.E.P.); (I.P.); (H.K.)
| | - Hyunee Yim
- Department of Pathology, Ajou University School of Medicine, Suwon 16499, Republic of Korea;
| | - Ji Eun Park
- Department of Nephrology, Ajou University School of Medicine, Suwon 16499, Republic of Korea; (M.-J.L.); (J.E.P.); (I.P.); (H.K.)
- Department of Endocrinology & Metabolism, Ajou University School of Medicine, Suwon 16499, Republic of Korea
| | - Inwhee Park
- Department of Nephrology, Ajou University School of Medicine, Suwon 16499, Republic of Korea; (M.-J.L.); (J.E.P.); (I.P.); (H.K.)
| | - Heungsoo Kim
- Department of Nephrology, Ajou University School of Medicine, Suwon 16499, Republic of Korea; (M.-J.L.); (J.E.P.); (I.P.); (H.K.)
| | - Gyu-Tae Shin
- Department of Nephrology, Ajou University School of Medicine, Suwon 16499, Republic of Korea; (M.-J.L.); (J.E.P.); (I.P.); (H.K.)
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Zhang D, Li Y, Liang M, Liang Y, Tian J, He Q, Yang B, Jin J, Zhu W. LC-MS/MS based metabolomics and proteomics reveal candidate biomarkers and molecular mechanism of early IgA nephropathy. Clin Proteomics 2022; 19:51. [PMID: 36572849 PMCID: PMC9793667 DOI: 10.1186/s12014-022-09387-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 12/07/2022] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Immunoglobulin A nephropathy (IgAN), a globally common primary chronic glomerulopathy, is one of the leading causes of end-stage renal disease. However, the underlying mechanisms of IgAN have yet to be demonstrated. There were no adequate and reliable plasma biomarkers for clinical diagnosis, especially at the early stage. In the present study, integrative proteomics and metabolomics were aimed at exploring the mechanism of IgAN and identifying potential biomarkers. METHODS Plasma from IgAN and healthy individuals were collected and analyzed in a randomized controlled manner. Data-independent acquisition quantification proteomics and mass spectrometry based untargeted metabolomics techniques were used to profile the differentially expressed proteins (DEPs) and differentially abundant metabolites (DAMs) between two groups and identify potential biomarkers for IgAN from health at the early stage. Disease-related pathways were screened out by clustering and function enrichment analyses of DEPs and DAMs. And the potential biomarkers for IgAN were identified through the machine learning approach. Additionally, an independent cohort was used to validate the priority candidates by enzyme-linked immunosorbent assay (ELISA). RESULTS Proteomic and metabolomic analyses of IgAN plasma showed that the complement and the immune system were activated, while the energy and amino acid metabolism were disordered in the IgAN patients. PRKAR2A, IL6ST, SOS1, and palmitoleic acid have been identified as potential biomarkers. Based on the AUC value for the training and test sets, the classification performance was 0.994 and 0.977, respectively. The AUC of the external validation of the four biomarkers was 0.91. CONCLUSION In this study, we combined proteomics and metabolomics techniques to analyze the plasma of IgAN patients and healthy individuals, constructing a biomarker panel, which could provide new insights and provide potential novel molecular diagnoses for IgAN.
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Affiliation(s)
- Di Zhang
- Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, 310014 Zhejiang China
| | - Yaohan Li
- grid.13402.340000 0004 1759 700XCollege of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou, 310027 Zhejiang China ,grid.410726.60000 0004 1797 8419The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310002 Zhejiang China
| | - Mingzhu Liang
- Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, 310014 Zhejiang China
| | - Yan Liang
- Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, 310014 Zhejiang China
| | - Jingkui Tian
- grid.410726.60000 0004 1797 8419The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310002 Zhejiang China
| | - Qiang He
- grid.417400.60000 0004 1799 0055Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, 310000 Zhejiang China
| | - Bingxian Yang
- grid.413273.00000 0001 0574 8737College of Life Science and Medicine, Zhejiang Sci-Tech University, Hangzhou, 310018 China
| | - Juan Jin
- Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, 310014 Zhejiang China
| | - Wei Zhu
- grid.410726.60000 0004 1797 8419The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310002 Zhejiang China
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Xiao M, Medipally AK, Biederman L, Satoskar AA, Ivanov I, Rovin BH, Brodsky SV. Chronic Hematuria Increases Chronic Kidney Injury and Epithelial-Mesenchymal Transition in 5/6 Nephrectomy Rats. Front Med (Lausanne) 2021; 8:753506. [PMID: 34901065 PMCID: PMC8655688 DOI: 10.3389/fmed.2021.753506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 10/19/2021] [Indexed: 11/29/2022] Open
Abstract
Chronic kidney disease (CKD) is a common outcome of many kidney diseases. Interstitial fibrosis and tubular atrophy (IFTA) is a histologic hallmark of CKD. Hematuria is a common symptom in many human kidney diseases. Free hemoglobin may affect tubular epithelial cells by generating reactive oxygen species (ROS). Epithelial–mesenchymal transition (EMT) of the tubular epithelial cells has been shown to play an important role in the IFTA development. The aim of this study was to determine the effects of chronic hematuria on the CKD progression in 5/6 nephrectomy (5/6NE) rat model of CKD. 5/6 NE rats were treated with oral warfarin (0.5 mg/kg/day) or vehicle (control). The animals were monitored for 26 weeks, while prothrombin time (PT), serum creatinine (SCr), and hematuria were measured weekly. Staining for iron, trichrome, and EMT (vimentin, E-cadherin, smooth muscle actin) markers was performed on the remnant kidneys. ROS were detected in the kidneys by protein carbonyl assay and immunohistochemistry for heme oxygenase 1 (HMOX1), at the end of the study. Apoptosis was detected by TUNEL assay. Warfarin treatment resulted in a PT increase 1.5–2.5 times from control and an increase in hematuria and SCr. Histologically, warfarin-treated animals had more iron-positive tubular epithelial cells and increased IFTA as compared to control (42.9 ± 17% vs. 18.3 ± 2.6%). ROS were increased in the kidney in warfarin-treated rats. The number of tubules that show evidence of EMT was significantly higher in warfarin-treated 5/6NE as compared to control 5/6NE rats. The number of apoptotic tubular epithelial cells was higher in warfarin-treated 5/6 NE rats. Chronic hematuria results in increased iron-positive tubular epithelial cells, EMT, apoptosis, and more prominent IFTA in CKD rats. Our data suggest an important role of chronic hematuria in the progression of CKD.
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Affiliation(s)
- Min Xiao
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Ajay K Medipally
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Laura Biederman
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United States.,Department of Pathology, Nationwide Children Hospital, Columbus, OH, United States
| | - Anjali A Satoskar
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Iouri Ivanov
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Brad H Rovin
- Department of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Sergey V Brodsky
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United States
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Wang Q, Dai X, Xiang X, Xu Z, Su S, Wei D, Zheng T, Shang EX, Qian D, Duan JA. A natural product of acteoside ameliorate kidney injury in diabetes db/db mice and HK-2 cells via regulating NADPH/oxidase-TGF-β/Smad signaling pathway. Phytother Res 2021; 35:5227-5240. [PMID: 34236110 DOI: 10.1002/ptr.7196] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 04/10/2021] [Accepted: 04/26/2021] [Indexed: 11/06/2022]
Abstract
This study was designed to investigate the protective effects and mechanisms of acteoside on DKD in diabetes male db/db mice and high glucose-induced HK-2 cells. The diabetes db/db mice were divided randomly into model group, metformin group, irbesartan group, and acteoside group. We observed the natural product of acteoside exhibiting a significant effect in renal protection through analyzing of biochemical indicators and endogenous metabolites, histopathological observations, and western blotting. HK-2 cells subjected to high glucose were used in invitro experiments. The molecular mechanisms of them were investigated by RT-PCR and western blot. Acteoside prevents high glucose-induced HK-2 cells and diabetes db/db mice by inhibiting NADPH/oxidase-TGF-β/Smad signaling pathway. Acteoside regulated the disturbed metabolic pathway of lipid metabolism, glyoxylate and dicarboxylate metabolism, and arachidonic acid metabolism. We discovered the natural product of acteoside exhibiting a significant effect in renal protection. This study paved the way for further exploration of pathogenesis, early diagnosis, and development of a new therapeutic agent for DKD.
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Affiliation(s)
- Qinwen Wang
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, and National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, and Key Laboratory of Chinese Medicinal Resources Recycling Utilization, State Administration of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xinxin Dai
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, and National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, and Key Laboratory of Chinese Medicinal Resources Recycling Utilization, State Administration of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xiang Xiang
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, and National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, and Key Laboratory of Chinese Medicinal Resources Recycling Utilization, State Administration of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Zhuo Xu
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, and National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, and Key Laboratory of Chinese Medicinal Resources Recycling Utilization, State Administration of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Shulan Su
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, and National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, and Key Laboratory of Chinese Medicinal Resources Recycling Utilization, State Administration of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Dandan Wei
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, and National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, and Key Laboratory of Chinese Medicinal Resources Recycling Utilization, State Administration of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Tianyao Zheng
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, and National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, and Key Laboratory of Chinese Medicinal Resources Recycling Utilization, State Administration of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Er-Xin Shang
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, and National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, and Key Laboratory of Chinese Medicinal Resources Recycling Utilization, State Administration of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Dawei Qian
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, and National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, and Key Laboratory of Chinese Medicinal Resources Recycling Utilization, State Administration of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jin-Ao Duan
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, and National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, and Key Laboratory of Chinese Medicinal Resources Recycling Utilization, State Administration of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
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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.
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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
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Moore CL, Savenka AV, Basnakian AG. TUNEL Assay: A Powerful Tool for Kidney Injury Evaluation. Int J Mol Sci 2021; 22:ijms22010412. [PMID: 33401733 PMCID: PMC7795088 DOI: 10.3390/ijms22010412] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 12/23/2020] [Accepted: 12/28/2020] [Indexed: 02/06/2023] Open
Abstract
Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay is a long-established assay used to detect cell death-associated DNA fragmentation (3'-OH DNA termini) by endonucleases. Because these enzymes are particularly active in the kidney, TUNEL is widely used to identify and quantify DNA fragmentation and cell death in cultured kidney cells and animal and human kidneys resulting from toxic or hypoxic injury. The early characterization of TUNEL as an apoptotic assay has led to numerous misinterpretations of the mechanisms of kidney cell injury. Nevertheless, TUNEL is becoming increasingly popular for kidney injury assessment because it can be used universally in cultured and tissue cells and for all mechanisms of cell death. Furthermore, it is sensitive, accurate, quantitative, easily linked to particular cells or tissue compartments, and can be combined with immunohistochemistry to allow reliable identification of cell types or likely mechanisms of cell death. Traditionally, TUNEL analysis has been limited to the presence or absence of a TUNEL signal. However, additional information on the mechanism of cell death can be obtained from the analysis of TUNEL patterns.
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Affiliation(s)
- Christopher L. Moore
- Department of Pharmacology & Toxicology, University of Arkansas for Medical Sciences, 4301 West Markham Street, #638, Little Rock, AR 72205, USA; (C.L.M.); (A.V.S.)
| | - Alena V. Savenka
- Department of Pharmacology & Toxicology, University of Arkansas for Medical Sciences, 4301 West Markham Street, #638, Little Rock, AR 72205, USA; (C.L.M.); (A.V.S.)
| | - Alexei G. Basnakian
- Department of Pharmacology & Toxicology, University of Arkansas for Medical Sciences, 4301 West Markham Street, #638, Little Rock, AR 72205, USA; (C.L.M.); (A.V.S.)
- John L. McClellan Memorial VA Hospital, Central Arkansas Veterans Healthcare System, 4300 West 7th Street, Little Rock, AR 72205, USA
- Correspondence: ; Tel.: +1-501-352-2870
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7
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Mizdrak M, Filipović N, Vukojević K, Čapkun V, Mizdrak I, Durdov MG. Prognostic value of connective tissue growth factor and c-Myb expression in IgA nephropathy and Henoch-Schönlein purpura-A pilot immunohistochemical study. Acta Histochem 2020; 122:151479. [PMID: 31870504 DOI: 10.1016/j.acthis.2019.151479] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Revised: 11/16/2019] [Accepted: 11/18/2019] [Indexed: 12/31/2022]
Abstract
AIM Adverse and advanced prognostic signs in IgA nephropathy (IgAN) are interstitial fibrosis and tubular atrophy, but early predictors of bad outcome are still lacking. We investigated expression of connective tissue growth factor (CTGF) and c-Myb in renal biopsies of IgAN and Henoch-Schönlein purpura (HSP), because these gene products are indirectly included in fibrosis and epithelial-mesenchymal transition (EMT). METHODS The sample included 23 patients and 8 controls who underwent nephrectomy due to renal cancer. The slides cut from the paraffin blocks were prepared for standard indirect immunoflourescence, using antibodies to CTGF and c-Myb. Ten high-power non-overlapping fields were photographed on Olympus IX51 microscope. Average percent of positive tubular cells, as well as number of positive cells per glomerulus were calculated. RESULTS The cytoplasmic tubular CTGF expression was higher in IgAN/HSP than in controls (P < 0.001), whereas no difference was found in glomeruli (P = 0.437). The nuclear c-Myb expresssion in glomeruli and tubules was higher in IgAN/HSP than in controls (P < 0.05). In the follow-up, decline in renal function correlated with glomerular and tubular c-Myb, as well as tubular CTGF expression (all P < 0.05). CONCLUSION Our results proposed c-Myb and CTGF as novel, early and sensitive markers of chronic kidney disease and worse renal outcome, but larger series are needed.
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8
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Wu S, Guo H, Horng H, Liu Y, Li H, Daneshpajouhnejad P, Rosenberg A, Albanese C, Ranjit S, Andrews PM, Levi M, Tang Q, Chen Y. Morphological and functional characteristics of aging kidneys based on two-photon microscopy in vivo. JOURNAL OF BIOPHOTONICS 2020; 13:e201900246. [PMID: 31688977 DOI: 10.1002/jbio.201900246] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Revised: 09/29/2019] [Accepted: 10/29/2019] [Indexed: 05/08/2023]
Abstract
Age-related kidney disease, which is chronic and naturally occurring, is a general term for a set of heterogeneous disorders affecting kidney structures and characterized by a decline in renal function. Age-related renal insufficiency has important implications with regard to body homeostasis, drug toxicity and renal transplantation. In our study, two-photon microscopy was used to image kidney morphological and functional characteristics in an age-related rat model in vivo. The changes in morphology are analyzed based on autofluorescence and Hoechst 33342 labeling in rats with different ages. Structural parameters including renal tubular diameter, cell nuclei density, size and shape are studied and compared with Hematoxylin and Eosin histological analysis. Functional characteristics, such as blood flow, and glomerular filtration rate are studied with high-molecular weight (MW) 500-kDa dextran-fluorescein and low-MW 10-kDa dextran-rhodamine. Results indicate that morphology changes significantly and functional characteristics deteriorate with age. These parameters are potential indicators for evaluating age-related renal morphology and function changes. Combined analyses of these parameters could provide a quantitative, novel method for monitoring kidney diseases and/or therapeutic effects of kidney drugs.
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Affiliation(s)
- Shulian Wu
- Fujian Provincial Key Laboratory of Photonic Technology, Key Laboratory of Optoelectronic Science and Technology for Medicine, College of Photonic and Electronic Engineering, Fujian Normal University, Ministry of Education, Fuzhou, China
- Fischell Department of Bioengineering, University of Maryland, College Park, Maryland
| | - Hengchang Guo
- Fischell Department of Bioengineering, University of Maryland, College Park, Maryland
| | - Hannah Horng
- Fischell Department of Bioengineering, University of Maryland, College Park, Maryland
| | - Yi Liu
- Fischell Department of Bioengineering, University of Maryland, College Park, Maryland
| | - Hui Li
- Fujian Provincial Key Laboratory of Photonic Technology, Key Laboratory of Optoelectronic Science and Technology for Medicine, College of Photonic and Electronic Engineering, Fujian Normal University, Ministry of Education, Fuzhou, China
| | | | - Avi Rosenberg
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Christopher Albanese
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC
| | - Suman Ranjit
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC
| | - Peter M Andrews
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC
| | - Moshe Levi
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC
| | - Qinggong Tang
- Fischell Department of Bioengineering, University of Maryland, College Park, Maryland
- Stephenson School of Biomedical Engineering, University of Oklahoma, Norman, Oklahoma
| | - Yu Chen
- Fujian Provincial Key Laboratory of Photonic Technology, Key Laboratory of Optoelectronic Science and Technology for Medicine, College of Photonic and Electronic Engineering, Fujian Normal University, Ministry of Education, Fuzhou, China
- Fischell Department of Bioengineering, University of Maryland, College Park, Maryland
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9
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Prediction of renal outcome in Henoch-Schönlein nephritis based on biopsy findings. Pediatr Nephrol 2020; 35:659-668. [PMID: 31797094 PMCID: PMC7056733 DOI: 10.1007/s00467-019-04415-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Revised: 10/05/2019] [Accepted: 11/01/2019] [Indexed: 11/08/2022]
Abstract
BACKGROUND In Henoch-Schönlein nephritis (HSN), a risk factor for unfavorable outcome is prolonged proteinuria, but the value of renal biopsies in prognosis assessment is debatable. METHODS We evaluated serial renal biopsies from 26 HSN patients. Follow-up biopsy occurred at median 2.1 years after diagnostic biopsy. Patients formed two groups at the follow-up biopsy: patients without proteinuria (group I; n = 11) and with proteinuria (group II; n = 15). Biopsies underwent evaluation according to three classifications: International Study of Kidney Disease in Children (ISKDC), Oxford (MEST-C), and semiquantitative classification (SQC) including an activity and chronicity score. Analysis also included expression of pro-fibrotic (alpha-smooth muscle actin and vimentin) and inflammatory (P-selectin glycoprotein ligand-1) molecules in the diagnostic biopsy specimens. Definition of unfavorable outcome was active renal disease or reduced renal function at last follow-up. RESULTS Between the biopsies, SQC chronicity score increased in 22 (85%) patients, whereas activity score and ISKDC grade decreased in 21 (81%) and 17 (65%), respectively. Of the MEST-C parameters, endocapillary proliferation (from 83 to 13%; p < 0.001) and crescents (from 63 to 25%; p = 0.022) showed significant reduction, and segmental glomerulosclerosis (from 38 to 79%; p = 0.006) significant increment. These changes occurred similarly in groups I and II. Expression of the pro-fibrotic and inflammatory molecules showed no clinically significant differences between groups I and II. None in group I and five (33%) patients in group II had unfavorable outcome (p = 0.053). CONCLUSIONS Our results suggest that follow-up biopsies provide limited additional information to clinical symptoms in HSN outcome prediction.
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Matrix-assisted laser desorption/ionization mass spectrometry imaging to uncover protein alterations associated with the progression of IgA nephropathy. Virchows Arch 2019; 476:903-914. [PMID: 31838587 DOI: 10.1007/s00428-019-02705-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 09/27/2019] [Accepted: 10/22/2019] [Indexed: 02/07/2023]
Abstract
IgA nephropathy (IgAN) is one of the most diffuse glomerulonephrites worldwide, and many issues still remain regarding our understanding of its pathogenesis. The disease is diagnosed by renal biopsy examination, but potential pitfalls still persist with regard to discriminating its primary origin and, as a result, determining patient outcome remains challenging. In this pilot study, matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) was performed on renal biopsies obtained from patients with IgAN (n = 11) and other mesangioproliferative glomerulonephrites (MesPGN, n = 6) in order to enlighten proteomic alterations that may be associated with the progression of IgAN. Differences in the proteomic profiles of IgAN and MesPGN tissue could clearly be detected using this approach and, furthermore, 14 signals (AUC ≥ 0.8) were observed to have an altered intensity among the different CKD stages within the IgAN group. In particular, large increases in the intensity of these signals could be observed at CKD stages II and above. These signals primarily corresponded to proteins involved in either inflammatory and healing pathways and their increased intensity was localized within regions of tissue with large amounts of inflammatory cells or sclerosis. Despite much work in recent years, our molecular understanding of IgAN progression remains incomplete. This pilot study represents a promising starting point in the search for novel protein markers that can assist clinicians in better understanding the pathogenesis of IgAN and highlighting those patients who may progress to end-stage renal disease.
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11
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Huang F, Zhao Y, Wang Q, Hillebrands JL, van den Born J, Ji L, An T, Qin G. Dapagliflozin Attenuates Renal Tubulointerstitial Fibrosis Associated With Type 1 Diabetes by Regulating STAT1/TGFβ1 Signaling. Front Endocrinol (Lausanne) 2019; 10:441. [PMID: 31333586 PMCID: PMC6616082 DOI: 10.3389/fendo.2019.00441] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2018] [Accepted: 06/18/2019] [Indexed: 12/12/2022] Open
Abstract
Tubulointerstitial fibrosis (TIF) plays an important role in the progression of renal fibrosis in diabetic nephropathy (DN). Accumulating evidence supports a crucial inhibitory effect of dapagliflozin, a SGLT2 inhibitor, on TIF, but the underlying mechanisms remain largely unknown. This study aimed to shed light on the efficacy of dapagliflozin in reducing TIF as well as its possible impact on renal function. TIF in human kidney biopsies obtained from patients with DN was quantified by histopathological staining. In vitro, HK-2 cells were incubated in high glucose with dapagliflozin or fludarabine, and epithelial-mesenchymal transition (EMT) was determined. In vivo experiments were performed in streptozotocin (STZ)-induced type 1 diabetic mice treated with dapagliflozin by gavage for 16 weeks, after which specific functional characteristics and TIF were analyzed. In both DN patients and diabetic mice, fibronectin and Col IV, as well as STAT1 protein in the kidneys were increased as compared with controls. Dapagliflozin significantly decreased blood glucose, and renal STAT1 and TGF-β1 expression in mice. Furthermore, dapagliflozin improved renal function, and attenuated diabetes-induced TIF. In HK-2 cells, dapagliflozin, and fludarabine directly decreased aberrant STAT1 expression and reversed high glucose-induced downregulation of E-cadherin and α-SMA induction. Thus, the results demonstrate that dapagliflozin not only improves hyperglycemia but also slows down the progression of diabetes-associated renal TIF by improving hyperglycemia-induced activation of the STAT1/TGF-β1 pathway.
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Affiliation(s)
- Fengjuan Huang
- Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Division of Pathology, Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Yanyan Zhao
- Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Qingzhu Wang
- Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jan-Luuk Hillebrands
- Division of Pathology, Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Jacob van den Born
- Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Linlin Ji
- Division of Pathology, Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Tingting An
- Division of Pathology, Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Guijun Qin
- Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- *Correspondence: Guijun Qin
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LncRNA-NR_033515 promotes proliferation, fibrogenesis and epithelial-to-mesenchymal transition by targeting miR-743b-5p in diabetic nephropathy. Biomed Pharmacother 2018; 106:543-552. [DOI: 10.1016/j.biopha.2018.06.104] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Revised: 06/17/2018] [Accepted: 06/18/2018] [Indexed: 01/10/2023] Open
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13
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Dexmedetomidine Ameliorates Acute Stress-Induced Kidney Injury by Attenuating Oxidative Stress and Apoptosis through Inhibition of the ROS/JNK Signaling Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:4035310. [PMID: 30250633 PMCID: PMC6140004 DOI: 10.1155/2018/4035310] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Revised: 07/26/2018] [Accepted: 08/02/2018] [Indexed: 12/18/2022]
Abstract
Acute stress induces tissue damage through excessive oxidative stress. Dexmedetomidine (DEX) reportedly has an antioxidant effect. However, protective roles and related potential molecular mechanisms of DEX against kidney injury induced by acute stress are unknown. Herein, rats were forced to swim 15 min followed by restraint stress for 3 h with/without DEX (30 μg/kg). Successful model establishment was validated by an open-field test. Assessment of renal function (creatinine, urea nitrogen), histopathology, oxidative stress (malondialdehyde, glutathione, and superoxide dismutase), and apoptosis (transferase-mediated dUTP nick end labeling) was performed. Localization of apoptosis was determined by immunohistochemistry of cleaved caspase 3 protein. In addition, key proteins of the death receptor-mediated pathway, mitochondrial pathway, endoplasmic reticulum stress (ERS) pathway, and ROS/JNK signaling pathway were measured by Western blot. We found that DEX significantly improved renal dysfunction, ameliorated kidney injury, reduced oxidative stress, and alleviated apoptosis. DEX also inhibited the release of norepinephrine (NE), decreased the production of reactive oxygen species (ROS), and inhibited JNK phosphorylation. Additionally, DEX downregulated the expression of Bax, cytochrome C, cleaved caspase 9, and cleaved caspase 3 proteins in mitochondria-dependent pathways. In summary, DEX protects against acute stress-induced kidney injury in rats by reducing oxidative stress and apoptosis via inhibition of the ROS/JNK pathway.
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14
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Bai Y, Han G, Guo K, Yu L, Du X, Xu Y. Effect of lentiviral vector-mediated KSR1 gene silencing on the proliferation of renal tubular epithelial cells and expression of inflammatory factors in a rat model of ischemia/reperfusion injury. Acta Biochim Biophys Sin (Shanghai) 2018; 50:807-816. [PMID: 30020400 DOI: 10.1093/abbs/gmy071] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Accepted: 05/31/2018] [Indexed: 11/14/2022] Open
Abstract
Renal ischemia/reperfusion (I/R) is a common cause of acute renal failure in many clinical settings. Our study aimed to elucidate the role of lentiviral vector-mediated KSR1 gene silencing in inflammatory factor expression and proliferation of renal tubular epithelial cells (RTECs) in a rat model of I/R injury. Male Sprague-Dawley (SD) rats were used for I/R model establishment and subject to different treatments, followed by the measurement of neurological severity score (NSS), tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-1β, 47-kDa heat-shock protein (HSP47), KSR1, and factors related to the Ras/MAPK pathway, as well as cell apoptosis. As compared with the blank group, the neurologic impairment induced by I/R in the siKSR1, U0126, and siKSR1 + U0126 groups was alleviated. Compared with the control group, the other five groups showed increased levels of TNF-α, IL-6, IL-1β, HSP47, N-ras, Raf-1, c-fos, TNF-α, IL-6, p38 MAPK, and cell apoptosis, accompanied by a declined mRNA and protein level of Bcl-2. As compared with the blank and NC groups, the siKSR1, U0126, and siKSR1 + U0126 groups showed decreased levels of TNF-α, IL-6, IL-1β, HSP47, N-ras, Raf-1, c-fos, TNF-α, IL-6, p38 MAPK, cleaved caspase-3, cleaved caspase-9, p53, and cell apoptosis, accompanied by an increased mRNA and protein level of Bcl-2. Our findings demonstrated that KSR1 gene silencing might inhibit the expression of inflammatory factors in RTECs and promote their proliferation by inactivating the Ras/MAPK pathway in the rat model of I/R injury.
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Affiliation(s)
- Yang Bai
- Department of Ultrasound, The First Hospital of Jilin University, Changchun, China
| | - Guanghong Han
- Department of Oral Geriatrics, School and Hospital of Stomatology, Jilin University, Changchun, China
| | - Kaimin Guo
- Department of Andrology, The First Hospital of Jilin University, Changchun, China
| | - Lili Yu
- Social Development Bureau, Changchun Jingyue High-Tech Industrial Development Zone Management Committee, Changchun, China
| | - Xiadong Du
- Department of Ultrasound, The First Hospital of Jilin University, Changchun, China
| | - Ying Xu
- Department of Nephrology, The First Hospital of Jilin University, Changchun, China
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15
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Li SS, He AL, Deng ZY, Liu QF. Ginsenoside-Rg1 Protects against Renal Fibrosis by Regulating the Klotho/TGF-β1/Smad Signaling Pathway in Rats with Obstructive Nephropathy. Biol Pharm Bull 2018; 41:585-591. [DOI: 10.1248/bpb.b17-00934] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Sha-sha Li
- Clinical Research & Lab Centre, Kunshan First People’s Hospital Affiliated to Jiangsu University
| | - Ao-lin He
- Clinical Research & Lab Centre, Kunshan First People’s Hospital Affiliated to Jiangsu University
| | - Zhi-yong Deng
- Department of Pathology, Kunshan First People’s Hospital Affiliated to Jiangsu University
| | - Qi-feng Liu
- Department of Nephrology, Kunshan First People’s Hospital Affiliated to Jiangsu University
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Liang S, Cai GY, Duan ZY, Liu SW, Wu J, Lv Y, Hou K, Li ZX, Zhang XG, Chen XM. Urinary sediment miRNAs reflect tubulointerstitial damage and therapeutic response in IgA nephropathy. BMC Nephrol 2017; 18:63. [PMID: 28201996 PMCID: PMC5312444 DOI: 10.1186/s12882-017-0482-0] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2016] [Accepted: 02/09/2017] [Indexed: 12/18/2022] Open
Abstract
Background Immunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis worldwide. The clinical spectrum of IgAN varies from minor urinary abnormalities to rapidly progressive renal failure. Evaluation of the disease by repeated renal biopsy is not practical due to its invasive procedure. Urinary sediment miRNAs promise to serve as non-invasive biomarkers to assess kidney injury of IgAN. Methods Fifty two biopsy-proven IgAN patients and twenty five healthy controls were enrolled in the study. Urinary sediment miRNAs were extracted. Expressions of miR-34a, miR-205, miR-21, miR-146a and miR-155 were quantified by real-time quantitative polymerase chain reaction (RT-QPCR). The receiver operating characteristic (ROC) curve was used to investigate the value of the miRNAs for predicting diagnosis of IgAN and evaluating histopathological injury. The patients were treated according to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines and followed up. The roles of miRNAs in reflecting therapeutic efficacy and disease progression were analyzed. Results 1. The IgAN group had significantly lower urinary miR-34a, miR-205, and miR-155, but higher miR-21 levels than controls. The ROC revealed that urinary miR-34a ≤ 0.047, miR-205 ≤ 0.209, miR-21 ≥ 0.461 and miR-155 ≤ 0.002 could distinguish patients with IgAN from healthy ones. In addition, miR-205 ≤ 0.125 and miR-21 ≥ 0.891 can distinguish IgAN patients with severe tubular atrophy/interstitial fibrosis from those with mild tubular atrophy/interstitial fibrosis. 2. After a mean 15.19 months follow-up, the reduction of proteinuria (g/24 h/year) was positively correlated with baseline urinary miR-21 and inversely correlated with miR-205. The levels of baseline eGFR and miR-205 in the complete remission group were significantly higher than non-complete remission group (p < 0.001; p = 0.018), while proteinuria, miR-21 and miR-146a were lower than non-complete remission group (p = 0.002; p = 0.021; p = 0.009). But multivariate analysis revealed that only baseline eGFR correlated with the remission of IgAN (p = 0.001, OR = 1.042). Conclusions The levels of some urinary sediment miRNAs, especially baseline miR-21 and miR-205, may be used as potential prognostic markers for evaluating the tubulointerstitial damage of IgAN. Furthermore, baseline levels of urinary miRNAs may be predictors of therapeutic efficacy and disease progression. Electronic supplementary material The online version of this article (doi:10.1186/s12882-017-0482-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Shuang Liang
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, 28 Fuxing Road, Beijing, 100853, China
| | - Guang-Yan Cai
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, 28 Fuxing Road, Beijing, 100853, China.
| | - Zhi-Yu Duan
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, 28 Fuxing Road, Beijing, 100853, China
| | - Shu-Wen Liu
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, 28 Fuxing Road, Beijing, 100853, China
| | - Jie Wu
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, 28 Fuxing Road, Beijing, 100853, China
| | - Yang Lv
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, 28 Fuxing Road, Beijing, 100853, China
| | - Kai Hou
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, 28 Fuxing Road, Beijing, 100853, China
| | - Zuo-Xiang Li
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, 28 Fuxing Road, Beijing, 100853, China
| | - Xue-Guang Zhang
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, 28 Fuxing Road, Beijing, 100853, China
| | - Xiang-Mei Chen
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, 28 Fuxing Road, Beijing, 100853, China
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Salvadori M, Rosso G. Update on immunoglobulin A nephropathy, Part I: Pathophysiology. World J Nephrol 2015; 4:455-467. [PMID: 26380197 PMCID: PMC4561843 DOI: 10.5527/wjn.v4.i4.455] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Revised: 08/24/2015] [Accepted: 08/30/2015] [Indexed: 02/06/2023] Open
Abstract
Immunoglobulin A (IgA) nephropathy is one of the most common glomerulonephritis and its frequency is probably underestimated because in most patients the disease has an indolent course and the kidney biopsy is essential for the diagnosis. In the last years its pathogenesis has been better identified even if still now several questions remain to be answered. The genetic wide association studies have allowed to identifying the relevance of genetics and several putative genes have been identified. The genetics has also allowed explaining why some ancestral groups are affected with higher frequency. To date is clear that IgA nephropathy is related to auto antibodies against immunoglobulin A1 (IgA1) with poor O-glycosylation. The role of mucosal infections is confirmed, but which are the pathogens involved and which is the role of Toll-like receptor polymorphism is less clear. Similarly to date whether the disease is due to the circulating immunocomplexes deposition on the mesangium or whether the antigen is already present on the mesangial cell as a "lanthanic" deposition remains to be clarified. Finally also the link between the mesangial and the podocyte injury and the tubulointerstitial scarring, as well as the mechanisms involved need to be better clarified.
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