Skip to main content
Top
Published in: BMC Nephrology 1/2016

Open Access 01-12-2016 | Research article

Crucial genes associated with diabetic nephropathy explored by microarray analysis

Authors: Zhikui Wang, Zhaoxia Wang, Zhongqi Zhou, Yueqin Ren

Published in: BMC Nephrology | Issue 1/2016

Login to get access

Abstract

Background

This study sought to investigate crucial genes correlated with diabetic nephropathy (DN), and their potential functions, which might contribute to a better understanding of DN pathogenesis.

Methods

The microarray dataset GSE1009 was downloaded from Gene Expression Omnibus, including 3 diabetic glomeruli samples and 3 healthy glomeruli samples. The differentially expressed genes (DEGs) were identified by LIMMA package. Their potential functions were then analyzed by the GO and KEGG pathway enrichment analyses using the DAVID database. Furthermore, miRNAs and transcription factors (TFs) regulating DEGs were predicted by the GeneCoDis tool, and miRNA-DEG-TF regulatory network was visualized by Cytoscape. Additionally, the expression of DEGs was validated using another microarray dataset GSE30528.

Results

Totally, 14 up-regulated DEGs and 430 down-regulated ones were identified. Some DEGs (e.g. MTSS1, CALD1 and ACTN4) were markedly relative to cytoskeleton organization. Besides, some other ones were correlated with arrhythmogenic right ventricular cardiomyopathy (e.g. ACTN4, CTNNA1 and ITGB5), as well as complement and coagulation cascades (e.g. C1R and C1S). Furthermore, a series of miRNAs and TFs modulating DEGs were identified. The transcription factor LEF1 regulated the majority of DEGs, such as ITGB5, CALD1 and C1S. Hsa-miR-33a modulated 28 genes, such as C1S. Additionally, 143 DEGs (one upregulated gene and 142 downregulated genes) were also differentially expressed in another dataset GSE30528.

Conclusions

The genes involved in cytoskeleton organization, cardiomyopathy, as well as complement and coagulation cascades may be closely implicated in the progression of DN, via the regulation of miRNAs and TFs.
Appendix
Available only for authorised users
Literature
1.
go back to reference Schor N, Ichikawa I, Rennke HG, Troy JL, Brenner BM. Pathophysiology of altered glomerular function in aminoglycoside-treated rats. Kidney Int. 1981;19(2):288–96.CrossRefPubMed Schor N, Ichikawa I, Rennke HG, Troy JL, Brenner BM. Pathophysiology of altered glomerular function in aminoglycoside-treated rats. Kidney Int. 1981;19(2):288–96.CrossRefPubMed
2.
go back to reference Inoki K, Corradetti MN, Guan K-L. Dysregulation of the TSC-mTOR pathway in human disease. Nat Genet. 2004;37(1):19–24.CrossRef Inoki K, Corradetti MN, Guan K-L. Dysregulation of the TSC-mTOR pathway in human disease. Nat Genet. 2004;37(1):19–24.CrossRef
3.
go back to reference Inoki K, Mori H, Wang J, Suzuki T, Hong S, Yoshida S, et al. mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice. J Clin Invest. 2011;121(6):2181–96.CrossRefPubMedPubMedCentral Inoki K, Mori H, Wang J, Suzuki T, Hong S, Yoshida S, et al. mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice. J Clin Invest. 2011;121(6):2181–96.CrossRefPubMedPubMedCentral
4.
go back to reference Gödel M, Hartleben B, Herbach N, Liu S, Zschiedrich S, Lu S, et al. Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. J Clin Invest. 2011;121(6):2197–209.CrossRefPubMedPubMedCentral Gödel M, Hartleben B, Herbach N, Liu S, Zschiedrich S, Lu S, et al. Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. J Clin Invest. 2011;121(6):2197–209.CrossRefPubMedPubMedCentral
5.
go back to reference Rooney B, O’Donovan H, Gaffney A, Browne M, Faherty N, Curran SP, et al. CTGF/CCN2 activates canonical Wnt signalling in mesangial cells through LRP6: implications for the pathogenesis of diabetic nephropathy. FEBS Lett. 2011;585(3):531–38.CrossRefPubMed Rooney B, O’Donovan H, Gaffney A, Browne M, Faherty N, Curran SP, et al. CTGF/CCN2 activates canonical Wnt signalling in mesangial cells through LRP6: implications for the pathogenesis of diabetic nephropathy. FEBS Lett. 2011;585(3):531–38.CrossRefPubMed
6.
go back to reference Giacco F, Du X, D’Agati VD, Milne R, Sui G, Geoffrion M, et al. Knockdown of glyoxalase 1 mimics diabetic nephropathy in nondiabetic mice. Diabetes. 2014;63(1):291–99.CrossRefPubMed Giacco F, Du X, D’Agati VD, Milne R, Sui G, Geoffrion M, et al. Knockdown of glyoxalase 1 mimics diabetic nephropathy in nondiabetic mice. Diabetes. 2014;63(1):291–99.CrossRefPubMed
7.
go back to reference Putta S, Lanting L, Sun G, Lawson G, Kato M, Natarajan R. Inhibiting microRNA-192 ameliorates renal fibrosis in diabetic nephropathy. J Am Soc Nephrol. 2012;23(3):458–69.CrossRefPubMedPubMedCentral Putta S, Lanting L, Sun G, Lawson G, Kato M, Natarajan R. Inhibiting microRNA-192 ameliorates renal fibrosis in diabetic nephropathy. J Am Soc Nephrol. 2012;23(3):458–69.CrossRefPubMedPubMedCentral
8.
go back to reference Baelde HJ, Eikmans M, Doran PP, Lappin DW, de Heer E, Bruijn JA. Gene expression profiling in glomeruli from human kidneys with diabetic nephropathy. Am J Kidney Dis. 2004;43(4):636–50.CrossRefPubMed Baelde HJ, Eikmans M, Doran PP, Lappin DW, de Heer E, Bruijn JA. Gene expression profiling in glomeruli from human kidneys with diabetic nephropathy. Am J Kidney Dis. 2004;43(4):636–50.CrossRefPubMed
9.
go back to reference Woroniecka KI, Park ASD, Mohtat D, Thomas DB, Pullman JM, Susztak K. Transcriptome analysis of human diabetic kidney disease. Diabetes. 2011;60(9):2354–69.CrossRefPubMedPubMedCentral Woroniecka KI, Park ASD, Mohtat D, Thomas DB, Pullman JM, Susztak K. Transcriptome analysis of human diabetic kidney disease. Diabetes. 2011;60(9):2354–69.CrossRefPubMedPubMedCentral
11.
go back to reference Smyth GK. Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol. 2004;3:Article3. Smyth GK. Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol. 2004;3:Article3.
12.
go back to reference Da Wei Huang BTS, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2008;4(1):44–57.CrossRef Da Wei Huang BTS, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2008;4(1):44–57.CrossRef
13.
go back to reference Mayes S, Ferrone M. Fentanyl HCl patient-controlled iontophoretic transdermal system for the management of acute postoperative pain. Ann Pharmacother. 2006;40(12):2178–86.CrossRefPubMed Mayes S, Ferrone M. Fentanyl HCl patient-controlled iontophoretic transdermal system for the management of acute postoperative pain. Ann Pharmacother. 2006;40(12):2178–86.CrossRefPubMed
14.
go back to reference Nogales-Cadenas R, Carmona-Saez P, Vazquez M, Vicente C, Yang X, Tirado F, et al. GeneCodis: interpreting gene lists through enrichment analysis and integration of diverse biological information. Nucleic Acids Res. 2009;37(Web Server issue):W317–22.CrossRefPubMedPubMedCentral Nogales-Cadenas R, Carmona-Saez P, Vazquez M, Vicente C, Yang X, Tirado F, et al. GeneCodis: interpreting gene lists through enrichment analysis and integration of diverse biological information. Nucleic Acids Res. 2009;37(Web Server issue):W317–22.CrossRefPubMedPubMedCentral
15.
go back to reference Kohl M, Wiese S, Warscheid B. Cytoscape: software for visualization and analysis of biological networks. In: Data Mining in Proteomics. New York: Springer; 2011. p. 291–303.CrossRef Kohl M, Wiese S, Warscheid B. Cytoscape: software for visualization and analysis of biological networks. In: Data Mining in Proteomics. New York: Springer; 2011. p. 291–303.CrossRef
17.
go back to reference Woodings J, Sharp S, Machesky L. MIM-B, a putative metastasis suppressor protein, binds to actin and to protein tyrosine phosphatase delta. Biochem J. 2003;37:463–71.CrossRef Woodings J, Sharp S, Machesky L. MIM-B, a putative metastasis suppressor protein, binds to actin and to protein tyrosine phosphatase delta. Biochem J. 2003;37:463–71.CrossRef
18.
go back to reference Erkan E, Garcia CD, Patterson LT, Mishra J, Mitsnefes MM, Kaskel FJ, et al. Induction of renal tubular cell apoptosis in focal segmental glomerulosclerosis: roles of proteinuria and Fas-dependent pathways. J Am Soc Nephrol. 2005;16(2):398–407.CrossRefPubMed Erkan E, Garcia CD, Patterson LT, Mishra J, Mitsnefes MM, Kaskel FJ, et al. Induction of renal tubular cell apoptosis in focal segmental glomerulosclerosis: roles of proteinuria and Fas-dependent pathways. J Am Soc Nephrol. 2005;16(2):398–407.CrossRefPubMed
19.
go back to reference Shankland S. The podocyte’s response to injury: role in proteinuria and glomerulosclerosis. Kidney Int. 2006;69(12):2131–47.CrossRefPubMed Shankland S. The podocyte’s response to injury: role in proteinuria and glomerulosclerosis. Kidney Int. 2006;69(12):2131–47.CrossRefPubMed
20.
go back to reference Ndozangue-Touriguine O, Hamelin J, Bréard J. Cytoskeleton and apoptosis. Biochem Pharmacol. 2008;76(1):11–8.CrossRefPubMed Ndozangue-Touriguine O, Hamelin J, Bréard J. Cytoskeleton and apoptosis. Biochem Pharmacol. 2008;76(1):11–8.CrossRefPubMed
21.
go back to reference Kaplan JM, Kim SH, North KN, Rennke H. Mutations in ACTN4, encoding α-actinin-4, cause familial focal segmental glomerulosclerosis. Nat Genet. 2000;24(3):251–56.CrossRefPubMed Kaplan JM, Kim SH, North KN, Rennke H. Mutations in ACTN4, encoding α-actinin-4, cause familial focal segmental glomerulosclerosis. Nat Genet. 2000;24(3):251–56.CrossRefPubMed
22.
go back to reference Dai S, Wang Z, Pan X, Wang W, Chen X, Ren H, et al. Functional analysis of promoter mutations in the ACTN4 and SYNPO genes in focal segmental glomerulosclerosis. Nephrol Dial Transpl. 2010;25(3):824–35.CrossRef Dai S, Wang Z, Pan X, Wang W, Chen X, Ren H, et al. Functional analysis of promoter mutations in the ACTN4 and SYNPO genes in focal segmental glomerulosclerosis. Nephrol Dial Transpl. 2010;25(3):824–35.CrossRef
23.
go back to reference Choi HJ, Lee BH, Cho HY, Moon KC, Ha IS, Nagata M, et al. Familial focal segmental glomerulosclerosis associated with an ACTN4 mutation and paternal germline mosaicism. Am J Kidney Dis. 2008;51(5):834–8.CrossRefPubMed Choi HJ, Lee BH, Cho HY, Moon KC, Ha IS, Nagata M, et al. Familial focal segmental glomerulosclerosis associated with an ACTN4 mutation and paternal germline mosaicism. Am J Kidney Dis. 2008;51(5):834–8.CrossRefPubMed
24.
go back to reference Ihalmo P, Wessman M, Kaunisto M, Kilpikari R, Parkkonen M, Forsblom C, et al. Association analysis of podocyte slit diaphragm genes as candidates for diabetic nephropathy. Diabetologia. 2008;51(1):86–90.CrossRefPubMed Ihalmo P, Wessman M, Kaunisto M, Kilpikari R, Parkkonen M, Forsblom C, et al. Association analysis of podocyte slit diaphragm genes as candidates for diabetic nephropathy. Diabetologia. 2008;51(1):86–90.CrossRefPubMed
25.
go back to reference Nakatani S, Kakehashi A, Ishimura E, Yamano S, Mori K, Wei M, et al. Targeted proteomics of isolated glomeruli from the kidneys of diabetic rats: sorbin and SH3 domain containing 2 is a novel protein associated with diabetic nephropathy. Exp Diabetes Res. 2011;2011:979354.CrossRefPubMedPubMedCentral Nakatani S, Kakehashi A, Ishimura E, Yamano S, Mori K, Wei M, et al. Targeted proteomics of isolated glomeruli from the kidneys of diabetic rats: sorbin and SH3 domain containing 2 is a novel protein associated with diabetic nephropathy. Exp Diabetes Res. 2011;2011:979354.CrossRefPubMedPubMedCentral
26.
go back to reference Novy RE, Lin J, Lin J. Characterization of cDNA clones encoding a human fibroblast caldesmon isoform and analysis of caldesmon expression in normal and transformed cells. J Biol Chem. 1991;266(25):16917–24.PubMed Novy RE, Lin J, Lin J. Characterization of cDNA clones encoding a human fibroblast caldesmon isoform and analysis of caldesmon expression in normal and transformed cells. J Biol Chem. 1991;266(25):16917–24.PubMed
27.
go back to reference Millioni R, Iori E, Lenzini L, Puricelli L, Caroccia B, Arrigoni G, et al. Caldesmon over-expression in type 1 diabetic nephropathy. J Diabetes Complications. 2011;25(2):114–21.CrossRefPubMed Millioni R, Iori E, Lenzini L, Puricelli L, Caroccia B, Arrigoni G, et al. Caldesmon over-expression in type 1 diabetic nephropathy. J Diabetes Complications. 2011;25(2):114–21.CrossRefPubMed
28.
go back to reference Conway BR, Maxwell AP, Savage DA, Patterson CC, Doran PP, Murphy M, et al. Association between variation in the actin-binding gene caldesmon and diabetic nephropathy in type 1 diabetes. Diabetes. 2004;53(4):1162–65.CrossRefPubMed Conway BR, Maxwell AP, Savage DA, Patterson CC, Doran PP, Murphy M, et al. Association between variation in the actin-binding gene caldesmon and diabetic nephropathy in type 1 diabetes. Diabetes. 2004;53(4):1162–65.CrossRefPubMed
29.
go back to reference Kim K, Lu Z, Hay ED. Direct evidence for a role of beta-catenin/LEF-1 signaling pathway in induction of EMT. Cell Biology Int. 2002;26(5):463–76.CrossRef Kim K, Lu Z, Hay ED. Direct evidence for a role of beta-catenin/LEF-1 signaling pathway in induction of EMT. Cell Biology Int. 2002;26(5):463–76.CrossRef
30.
go back to reference Cai L, Kang YJ. Oxidative stress and diabetic cardiomyopathy. Cardiovasc Toxicol. 2001;1(3):181–93.CrossRefPubMed Cai L, Kang YJ. Oxidative stress and diabetic cardiomyopathy. Cardiovasc Toxicol. 2001;1(3):181–93.CrossRefPubMed
31.
go back to reference McLean JW, Vestal D, Cheresh D, Bodary S. cDNA sequence of the human integrin beta 5 subunit. J Biol Chem. 1990;265(28):17126–31.PubMed McLean JW, Vestal D, Cheresh D, Bodary S. cDNA sequence of the human integrin beta 5 subunit. J Biol Chem. 1990;265(28):17126–31.PubMed
32.
go back to reference Gu HF, Ma J, Gu KT, Brismar K. Association of intercellular adhesion molecule 1 (ICAM1) with diabetes and diabetic nephropathy. Front Endocrinol (Lausanne). 2012;3:179. Gu HF, Ma J, Gu KT, Brismar K. Association of intercellular adhesion molecule 1 (ICAM1) with diabetes and diabetic nephropathy. Front Endocrinol (Lausanne). 2012;3:179.
33.
go back to reference Schumaker VN, Hanson DC, Kilchherr E, Phillips ML, Poon PH. A molecular mechanism for the activation of the first component of complement by immune complexes. Mol Immunol. 1986;23(5):557–65.CrossRefPubMed Schumaker VN, Hanson DC, Kilchherr E, Phillips ML, Poon PH. A molecular mechanism for the activation of the first component of complement by immune complexes. Mol Immunol. 1986;23(5):557–65.CrossRefPubMed
34.
go back to reference Galkina E, Ley K. Leukocyte recruitment and vascular injury in diabetic nephropathy. J Am Soc Nephrol. 2006;17(2):368–77.CrossRefPubMed Galkina E, Ley K. Leukocyte recruitment and vascular injury in diabetic nephropathy. J Am Soc Nephrol. 2006;17(2):368–77.CrossRefPubMed
35.
go back to reference Navarro-González JF, Mora-Fernández C, de Fuentes MM, García-Pérez J. Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy. Nat Rev Nephrol. 2011;7(6):327–40.CrossRefPubMed Navarro-González JF, Mora-Fernández C, de Fuentes MM, García-Pérez J. Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy. Nat Rev Nephrol. 2011;7(6):327–40.CrossRefPubMed
36.
go back to reference Wada J, Makino H. Inflammation and the pathogenesis of diabetic nephropathy. Clin Sci. 2013;124(3):139–52.CrossRefPubMed Wada J, Makino H. Inflammation and the pathogenesis of diabetic nephropathy. Clin Sci. 2013;124(3):139–52.CrossRefPubMed
37.
go back to reference Lim AK, Tesch GH. Inflammation in diabetic nephropathy. Mediat Inflamm. 2012;2012:146154.CrossRef Lim AK, Tesch GH. Inflammation in diabetic nephropathy. Mediat Inflamm. 2012;2012:146154.CrossRef
38.
go back to reference Zhang Z, Peng H, Chen J, Chen X, Han F, Xu X, et al. MicroRNA-21 protects from mesangial cell proliferation induced by diabetic nephropathy in db/db mice. FEBS letters. 2009;583(12):2009–14. Zhang Z, Peng H, Chen J, Chen X, Han F, Xu X, et al. MicroRNA-21 protects from mesangial cell proliferation induced by diabetic nephropathy in db/db mice. FEBS letters. 2009;583(12):2009–14.
39.
go back to reference Fechete R, Heinzel A, Perco P, Mönks K, Söllner J, Stelzer G, et al. Mapping of molecular pathways, biomarkers and drug targets for diabetic nephropathy. PROTEOMICS-Clinical Applications. 2011;5(5–6):354–66.CrossRefPubMed Fechete R, Heinzel A, Perco P, Mönks K, Söllner J, Stelzer G, et al. Mapping of molecular pathways, biomarkers and drug targets for diabetic nephropathy. PROTEOMICS-Clinical Applications. 2011;5(5–6):354–66.CrossRefPubMed
40.
go back to reference Dávalos A, Goedeke L, Smibert P, Ramírez CM, Warrier NP, Andreo U, et al. miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling. Proc Natl Acad Sci. 2011;108(22):9232–37.CrossRefPubMedPubMedCentral Dávalos A, Goedeke L, Smibert P, Ramírez CM, Warrier NP, Andreo U, et al. miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling. Proc Natl Acad Sci. 2011;108(22):9232–37.CrossRefPubMedPubMedCentral
41.
go back to reference Nikpour P, Miranzadeh-Mahabadi H, Emadi-Baygi M, Kelishadi R. Association of rs8066560 variant in the sterol regulatory element-binding protein 1 (SREBP-1) and miR-33b genes with hyperglycemia and insulin resistance. J Pediatr Endocr Met. 2014;27(7–8):611–5. Nikpour P, Miranzadeh-Mahabadi H, Emadi-Baygi M, Kelishadi R. Association of rs8066560 variant in the sterol regulatory element-binding protein 1 (SREBP-1) and miR-33b genes with hyperglycemia and insulin resistance. J Pediatr Endocr Met. 2014;27(7–8):611–5.
Metadata
Title
Crucial genes associated with diabetic nephropathy explored by microarray analysis
Authors
Zhikui Wang
Zhaoxia Wang
Zhongqi Zhou
Yueqin Ren
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Nephrology / Issue 1/2016
Electronic ISSN: 1471-2369
DOI
https://doi.org/10.1186/s12882-016-0343-2

Other articles of this Issue 1/2016

BMC Nephrology 1/2016 Go to the issue