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      Transcriptional Profile of Kidney from Type 2 Diabetic db/db Mice

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          Abstract

          Diabetic nephropathy (DN), a common diabetic microvascular complication, is characterized by progressive glomerular sclerosis and tubulointerstitial fibrosis. However, the underlying mechanisms involved in DN remain to be elucidated. We explored changes in the transcriptional profile in spontaneous type 2 diabetic db/db mice by using the cDNA microarray. Compared with control db/m mice, the db/db mice exhibited marked increases in body weight, kidney weight, and urinary albumin excretion. Renal histological analysis revealed mesangial expansion and thickness of the basement membrane in the kidney of the db/db mice. A total of 355 differentially expressed genes (DEGs) were identified by microarray analysis. Pathway enrichment analysis suggested that biological oxidation, bile acid metabolism, and steroid hormone synthesis were the 3 major significant pathways. The top 10 hub genes were selected from the constructed PPI network of DEGs, including Ccnb2 and Nr1i2, which remained largely unclear in DN. We believe that our study can help elucidate the molecular mechanisms underlying DN.

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          Transcriptome Analysis of Human Diabetic Kidney Disease

          OBJECTIVE Diabetic kidney disease (DKD) is the single leading cause of kidney failure in the U.S., for which a cure has not yet been found. The aim of our study was to provide an unbiased catalog of gene-expression changes in human diabetic kidney biopsy samples. RESEARCH DESIGN AND METHODS Affymetrix expression arrays were used to identify differentially regulated transcripts in 44 microdissected human kidney samples. DKD samples were significant for their racial diversity and decreased glomerular filtration rate (~25–35 mL/min). Stringent statistical analysis, using the Benjamini-Hochberg corrected two-tailed t test, was used to identify differentially expressed transcripts in control and diseased glomeruli and tubuli. Two different web-based algorithms were used to define differentially regulated pathways. RESULTS We identified 1,700 differentially expressed probesets in DKD glomeruli and 1,831 in diabetic tubuli, and 330 probesets were commonly differentially expressed in both compartments. Pathway analysis highlighted the regulation of Ras homolog gene family member A, Cdc42, integrin, integrin-linked kinase, and vascular endothelial growth factor signaling in DKD glomeruli. The tubulointerstitial compartment showed strong enrichment for inflammation-related pathways. The canonical complement signaling pathway was determined to be statistically differentially regulated in both DKD glomeruli and tubuli and was associated with increased glomerulosclerosis even in a different set of DKD samples. CONCLUSIONS Our studies have cataloged gene-expression regulation and identified multiple novel genes and pathways that may play a role in the pathogenesis of DKD or could serve as biomarkers.
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            Modular activation of nuclear factor-kappaB transcriptional programs in human diabetic nephropathy.

            Diabetic nephropathy (DN) is the leading cause of end-stage renal failure and a major risk factor for cardiovascular mortality in diabetic patients. To evaluate the multiple pathogenetic factors implicated in DN, unbiased mRNA expression screening of tubulointerstitial compartments of human renal biopsies was combined with hypothesis-driven pathway analysis. Expression fingerprints obtained from biopsies with histological diagnosis of DN (n = 13) and from control subjects (pretransplant kidney donors [n = 7] and minimal change disease [n = 4]) allowed us to segregate the biopsies by disease state and stage by the specific expression signatures. Functional categorization showed regulation of genes linked to inflammation in progressive DN. Pathway mapping of nuclear factor-kappaB (NF-kappaB), a master transcriptional switch in inflammation, segregated progressive from mild DN and control subjects by showing upregulation of 54 of 138 known NF-kappaB targets. The promoter regions of regulated NF-kappaB targets were analyzed using ModelInspector, and the NF-kappaB module NFKB_IRFF_01 was found to be specifically enriched in progressive disease. Using this module, the induction of eight NFKB_IRFF_01-dependant genes was correctly predicted in progressive DN (B2M, CCL5/RANTES, CXCL10/IP10, EDN1, HLA-A, HLA-B, IFNB1, and VCAM1). The identification of a specific NF-kappaB promoter module activated in the inflammatory stress response of progressive DN has helped to characterize upstream pathways as potential targets for the treatment of progressive renal diseases such as DN.
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              Characterization of the oxidative metabolites of 17beta-estradiol and estrone formed by 15 selectively expressed human cytochrome p450 isoforms.

              We systematically characterized the oxidative metabolites of 17beta-estradiol and estrone formed by 15 human cytochrome P450 (CYP) isoforms. CYP1A1 had high activity for 17beta-estradiol 2-hydroxylation, followed by 15alpha-, 6alpha-, 4-, and 7alpha-hydroxylation. However, when estrone was the substrate, CYP1A1 formed more 4-hydroxyestrone than 15alpha- or 6alpha-hydroxyestrone, with 2-hydroxyestrone as the major metabolite. CYP1A2 had the highest activity for the 2-hydroxylation of both 17beta-estradiol and estrone, although it also had considerable activity for their 4-hydroxylation (9-13% of 2-hydroxylation). CYP1B1 mainly catalyzed the formation of catechol estrogens, with 4-hydroxyestrogens predominant. CYP2A6, 2B6, 2C8, 2C9, 2C19, and 2D6 each showed a varying degree of low catalytic activity for estrogen 2-hydroxylation, whereas CYP2C18 and CYP2E1 did not show any detectable estrogen-hydroxylating activity. CYP3A4 had strong activity for the formation of 2-hydroxyestradiol, followed by 4-hydroxyestradiol and an unknown polar metabolite, and small amounts of 16alpha- and 16beta-hydroxyestrogens were also formed. The ratio of 4- to 2-hydroxylation of 17beta-estradiol or estrone with CYP3A4 was 0.22 or 0.51, respectively. CYP3A5 had similar catalytic activity for the formation of 2- and 4- hydroxyestrogens. Notably, CYP3A5 had an unusually high ratio of 4- to 2-hydroxylation of 17beta-estradiol or estrone (0.53 or 1.26, respectively). CYP3A4 and 3A5 also catalyzed the formation of nonpolar estrogen metabolite peaks (chromatographically less polar than estrone). CYP3A7 had a distinct catalytic activity for the 16alpha-hydroxylation of estrone, but not 17beta-estradiol. CYP4A11 had little catalytic activity for the metabolism of 17beta-estradiol and estrone. In conclusion, many human CYP isoforms are involved in the oxidative metabolism of 17beta-estradiol and estrone, with a varying degree of catalytic activity and distinct regioselectivity.
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                Author and article information

                Journal
                J Diabetes Res
                J Diabetes Res
                JDR
                Journal of Diabetes Research
                Hindawi Publishing Corporation
                2314-6745
                2314-6753
                2017
                23 January 2017
                : 2017
                : 8391253
                Affiliations
                1Beijing Key Lab Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
                2Department of Medical Research Center, International Science and Technology Cooperation Base of Geriatric Medicine, North China University of Science and Technology, Tangshan, China
                Author notes

                Academic Editor: Shuta Ishibe

                Author information
                http://orcid.org/0000-0002-5993-5260
                http://orcid.org/0000-0002-3315-2276
                Article
                10.1155/2017/8391253
                5292381
                2d916d09-bb33-4cbc-a7ad-73eff1ec487c
                Copyright © 2017 Haojun Zhang et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 30 September 2016
                : 7 December 2016
                Funding
                Funded by: International Collaboration in Science and Technology Grant, China
                Award ID: 2011DFA31860
                Funded by: National Natural Science Foundation of China
                Award ID: 81173422
                Award ID: 81373795
                Award ID: 81302942
                Award ID: 81473526
                Categories
                Research Article

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