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      SETD8 cooperates with MZF1 to participate in hyperglycemia-induced endothelial inflammation via elevation of WNT5A levels in diabetic nephropathy

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          Abstract

          Objective

          Diabetic nephropathy (DN) is regarded as the main vascular complication of diabetes mellitus, directly affecting the outcome of diabetic patients. Inflammatory factors were reported to participate in the progress of DN. Wingless-type family member 5 (WNT5A), myeloid zinc finger 1 (MZF1), and lysine methyltransferase 8 (SETD8) have also been reported to elevate inflammatory factor levels and activate the nuclear factor kappa B (NF-κB) pathway to induce endothelial dysfunction. In the current study, it was assumed that MZF1 associates with SETD8 to regulate WNT5A transcription, thus resulting in hyperglycemia-induced glomerular endothelial inflammation in DN.

          Methods

          The present study recruited 25 diagnosed DN patients (type 2 diabetes) and 25 control participants (nondiabetic renal cancer patients with normal renal function, stage I–II) consecutively. Moreover, a DN rat and cellular model was constructed in the present study. Immunohistochemistry, Western blot, and quantitative polymerase chain reaction (qPCR) were implemented to determine protein and messenger RNA (mRNA) levels. Coimmunoprecipitation (CoIP) and immunofluorescence were implemented in human glomerular endothelial cells (HGECs). Chromatin immunoprecipitation assays and dual luciferase assays were implemented to determine transcriptional activity.

          Results

          The results of this study indicated that levels of WNT5A expression, p65 phosphorylation (p-p65), and inflammatory factors were all elevated in DN patients and rats. In vitro, levels of p-p65 and inflammatory factors increased along with the increase of WNT5A expression in hyperglycemic HGECs. Moreover, high glucose increased MZF1 expression and decreased SETD8 expression. MZF1 and SETD8 inhibit each other under the stimulus of high glucose, but cooperate to regulate WNT5A expression, thus influencing p-p65 and endothelial inflammatory factors levels. Overexpression of MZF1 and silencing of SETD8 induced endothelial p-p65 and inflammatory factors levels, which can be reversed by si-WNT5A. Mechanistic research indicated that MZF1, SETD8, and its downstream target histone H4 lysine 20 methylation (H4K20me1) all occupied the WNT5A promoter region. sh-SETD8 expanded the enrichment of MZF1 on WNT5A promoter. Our in vivo study proved that SETD8 overexpression inhibited levels of WNT5A, p-p65 expression, and inflammatory factors in DN rats.

          Conclusions

          MZF1 links with SETD8 to regulate WNT5A expression in HGECs, thus elevating levels of hyperglycemia-mediated inflammatory factors in glomerular endothelium of DN patients and rats.

          Trial registration ChiCTR, ChiCTR2000029425. 2020/1/31, http://www.chictr.org.cn/showproj.aspx?proj=48548

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s11658-022-00328-6.

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          Most cited references35

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          Trends in Chronic Kidney Disease in China.

          Luxia Zhang, Jianyan Long, Wenshi Jiang … (2016)
          Article 0 comments Cited 333 times – based on 0 reviews     Review now
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            Diabetic kidney disease: a report from an ADA Consensus Conference.

            Katherine Tuttle, George L. Bakris, Rudolf W. Bilous … (2014)
            The incidence and prevalence of diabetes mellitus have grown significantly throughout the world, due primarily to the increase in type 2 diabetes. This overall increase in the number of people with diabetes has had a major impact on development of diabetic kidney disease (DKD), one of the most frequent complications of both types of diabetes. DKD is the leading cause of end-stage renal disease (ESRD), accounting for approximately 50% of cases in the developed world. Although incidence rates for ESRD attributable to DKD have recently stabilized, these rates continue to rise in high-risk groups such as middle-aged African Americans, Native Americans, and Hispanics. The costs of care for people with DKD are extraordinarily high. In the Medicare population alone, DKD-related expenditures among this mostly older group were nearly $25 billion in 2011. Due to the high human and societal costs, the Consensus Conference on Chronic Kidney Disease and Diabetes was convened by the American Diabetes Association in collaboration with the American Society of Nephrology and the National Kidney Foundation to appraise issues regarding patient management, highlighting current practices and new directions. Major topic areas in DKD included (1) identification and monitoring, (2) cardiovascular disease and management of dyslipidemia, (3) hypertension and use of renin-angiotensin-aldosterone system blockade and mineralocorticoid receptor blockade, (4) glycemia measurement, hypoglycemia, and drug therapies, (5) nutrition and general care in advanced-stage chronic kidney disease, (6) children and adolescents, and (7) multidisciplinary approaches and medical home models for health care delivery. This current state summary and research recommendations are designed to guide advances in care and the generation of new knowledge that will meaningfully improve life for people with DKD.
            Article 0 comments Cited 229 times – based on 0 reviews     Review now
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              Diabetes and Kidney Disease: Role of Oxidative Stress.

              Jay C Jha, Claudine Banal, Bryna S.M. Chow … (2016)
              Intrarenal oxidative stress plays a critical role in the initiation and progression of diabetic kidney disease (DKD). Enhanced oxidative stress results from overproduction of reactive oxygen species (ROS) in the context of concomitant, insufficient antioxidant pathways. Renal ROS production in diabetes is predominantly mediated by various NADPH oxidases (NOXs), but a defective antioxidant system as well as mitochondrial dysfunction may also contribute. Recent Advances: Effective agents targeting the source of ROS generation hold the promise to rescue the kidney from oxidative damage and prevent subsequent progression of DKD. Critical Issues and Future Directions: In the present review, we summarize and critically analyze molecular and cellular mechanisms that have been demonstrated to be involved in NOX-induced renal injury in diabetes, with particular focus on the role of increased glomerular injury, the development of albuminuria, and tubulointerstitial fibrosis, as well as mitochondrial dysfunction. Furthermore, novel agents targeting NOX isoforms are discussed. Antioxid. Redox Signal. 25, 657-684.
              Article 0 comments Cited 185 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Minmin Zhu:
                ORCID: http://orcid.org/0000-0002-4951-1421
                zhu_mm@126.com
                Changhong Miao: miao_chh@126.com
                Journal
                Journal ID (nlm-ta): Cell Mol Biol Lett
                Journal ID (iso-abbrev): Cell Mol Biol Lett
                Title: Cellular & Molecular Biology Letters
                Publisher: BioMed Central (London )
                ISSN (Print): 1425-8153
                ISSN (Electronic): 1689-1392
                Publication date (Electronic): 26 March 2022
                Publication date PMC-release: 26 March 2022
                Publication date Collection: 2022
                Volume: 27
                Electronic Location Identifier: 30
                Affiliations
                [1 ]GRID grid.8547.e, ISNI 0000 0001 0125 2443, Department of Anesthesiology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, , Fudan University, ; Shanghai, 200032 China
                [2 ]GRID grid.16821.3c, ISNI 0000 0004 0368 8293, Department of Anesthesiology, , Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, ; Shanghai, 200080 People’s Republic of China
                [3 ]GRID grid.413087.9, ISNI 0000 0004 1755 3939, Department of Anesthesiology, , Zhongshan Hospital, Fudan University, ; Shanghai, 200032 China
                Author information
                http://orcid.org/0000-0002-4951-1421
                Article
                Publisher ID: 328
                DOI: 10.1186/s11658-022-00328-6
                PMC ID: 8962284
                PubMed ID: 35350980
                SO-VID: 02fb7a7e-3c48-4c51-9c18-47b8488b0a09
                Copyright © © The Author(s) 2022
                License:

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 1 December 2021
                Date revision received : 14 February 2022
                Date accepted : 22 February 2022
                Categories
                Subject: Research
                Custom metadata
                issue-copyright-statement © The Author(s) 2022

                Keywords: diabetic nephropathy,setd8,endothelial
                Data availability:
                Keywords: diabetic nephropathy, setd8, endothelial

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