Endothelin-1 gene polymorphisms and diabetic kidney disease in patients with type 2 diabetes mellitus

Diabetology & Metabolic Syndrome

Luís H. Canani¹  Fernando Gerchman¹  Jorge L. Gross¹  Lucas P. Klassmann²  Denise A. Sortica²  Daisy Crispim¹  Claudete M. Zanatta² 

[1] Endocrine Division, Hospital de Clínicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil;Federal University of Rio Grande do Sul, Porto Alegre, Brazil

关键词: Diabetes mellitus type 2;    Diabetic kidney disease;    Endothelin-1;   

Others  :  1234352
DOI  :  10.1186/s13098-015-0093-5

 received in 2015-04-08, accepted in 2015-11-02,  发布年份 2015

【 摘 要 】

Background and aims

Diabetic kidney disease (DKD) is the leading cause of end stage renal disease worldwide and is associated with increased cardiovascular mortality. The endothelin system has been implicated in the pathogenesis of arterial hypertension and renal dysfunction. In the present study, the association of DKD with polymorphisms in ET-1 (EDN1) and ETRA (EDNRA) genes was analyzed in patients with type 2 diabetes mellitus (T2DM).

Methods

A case–control study was conducted in 548 white T2DM patients. Patients with proteinuria or on dialysis were considered cases and patients with normoalbuminuria were considered controls. Two polymorphisms in the EDN1 gene (rs1800541 and rs57072783) and five in EDNRA gene (rs6842241; rs4835083; rs4639051; rs5333 and rs5343) were genotyped and haplotype analyses were performed.

Results

The presence of rs57072783 T allele (TT/TG vs. GG) or rs1800541 G allele (GG/GT vs. TT) protected against DKD (OR = 0.69, 95 % CI 0.48–0.99, P = 0.049; and OR = 0.60, 95 % CI 0.41–0.88, P = 0.009, respectively). However in multivariate analyses, only the rs1800541 G allele remained independently associated with DKD (P = 0.046).

Conclusions

The present study shows that ET-1 could be involved in the pathogenesis of DKD in patients with T2DM.

【 授权许可】

   
2015 Zanatta et al.

【 参考文献 】

• [1]2014 National Chronic Kidney Disease Fact Sheet.. http://www.cdc.gov/diabetes/pubs/factsheets/kidney.htm#1 webcite
• [2]Valmadrid CT, Klein R, Moss SE, Klein BE: The risk of cardiovascular disease mortality associated with microalbuminuria and gross proteinuria in persons with older-onset diabetes mellitus. Arch Intern Med 2000, 160:1093-1100.
• [3]Craig KJ, Donovan K, Munnery M, Owens DR, Williams JD, Phillips AO: Identification and management of diabetic nephropathy in the diabetes clinic. Diabetes Care 2003, 26:1806-1811.
• [4]Barton M, Luscher TF: Endothelin antagonists for hypertension and renal disease. Curr Opin Nephrol Hypertens 1999, 8:549-556.
• [5]Levey AS, Coresh J, Balk E, Kausz AT, Levin A, Steffes MW, et al.: National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med 2003, 139:137-147.
• [6]Ohta K, Hirata Y, Shichiri M, Kanno K, Emori T, Tomita K, et al.: Urinary excretion of endothelin-1 in normal subjects and patients with renal disease. Kidney Int 1991, 39:307-311.
• [7]Benigni A, Perico N, Remuzzi G: Research on renal endothelin in proteinuric nephropathies dictates novel strategies to prevent progression. Curr Opin Nephrol Hypertens 1001, 10:1-6.
• [8]Hocher B, Schwarz A, Reinbacher D, Jacobi J, Lun A, Priem F, et al.: Effects of endothelin receptor antagonists on the progression of diabetic nephropathy. Nephron 2001, 87:161-169.
• [9]Sorokin A, Kohan DE: Physiology and pathology of endothelin-1 in renal mesangium. Am J Physiol Renal Physiol 2003, 285:F579-F589.
• [10]Gomez-Garre D, Ruiz-Ortega M, Ortego M, Largo R, Lopez-Armada MJ, Plaza JJ, et al.: Effects and interactions of endothelin-1 and angiotensin II on matrix protein expression and synthesis and mesangial cell growth. Hypertension 1996, 27:885-892.
• [11]Seligman BG, Biolo A, Polanczyk CA, Gross JL, Clausell N: Increased plasma levels of endothelin 1 and von Willebrand factor in patients with type 2 diabetes and dyslipidemia. Diabetes Care 2000, 23:1395-1400.
• [12]Schneider JG, Tilly N, Hierl T, Sommer U, Hamann A, Dugi K, et al.: Elevated plasma endothelin-1 levels in diabetes mellitus. Am J Hypertens 2002, 15:967-972.
• [13]De Mattia G, Cassone-Faldetta M, Bellini C, Bravi MC, Laurenti O, Baldoncini R, et al.: Role of plasma and urinary endothelin-1 in early diabetic and hypertensive nephropathy. Am J Hypertens 1998, 11:983-988.
• [14]Zanatta CM, Gerchman F, Burttet L, Nabinger G, Jacques-Silva MC, Canani LH, et al.: Endothelin-1 levels and albuminuria in patients with type 2 diabetes mellitus. Diabetes Res Clin Pract 2008, 80:299-304.
• [15]Zanatta CM, Veronese FV, Loreto MDS, Sortica DA, Carpio VN, Eldeweiss MI, et al.: Endothelin-1 and endothelin a receptor immunoreactivity is increased in patients with diabetic nephropathy. Ren Fail 2012, 34(3):308-315.
• [16]Canani LH, Costa LA, Crispim D, Goncalves Dos Santos K, Roisenberg I, Lisboa HR, et al.: The presence of allele D of angiotensin-converting enzyme polymorphism is associated with diabetic nephropathy in patients with less than 10 years duration of Type 2 diabetes. Diabet Med 2005, 22:1167-1172.
• [17]Zelmanovitz T, Gross JL, Oliveira JR, Paggi A, Tatsch M, Azevedo MJ: The receiver operating characteristics curve in the evaluation of a random urine specimen as a screening test for diabetic nephropathy. Diabetes Care 1997, 20:516-519.
• [18]Miller L, Gray L, Beachey E, Kehoe M: Antigenic variation among group A streptococcal M proteins. Nucleotide sequence of the serotype 5 M protein gene and its relationship with genes encoding types 6 and 24 M proteins. J Biol Chem 1988, 263:5668-5673.
• [19]The International HapMap project: Nature. 2003, 426:789-796.
• [20]Pinto-Sietsma SJ, Herrmann SM, Schmidt-Petersen K, Niu T, Hillege HL, Janssen WM, et al.: Role of the endothelin-1 gene locus for renal impairment in the general nondiabetic population. J Am Soc Nephrol 2003, 14:2596-2602.
• [21]Hedrick PW: Gametic disequilibrium measures: proceed with caution. Genetics 1987, 117:331-341.
• [22]Stephens M, Smith NJ, Donnelly P: A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001, 68:978-989.
• [23]Hopfner RL, Gopalakrishnan V: Endothelin: emerging role in diabetic vascular complications. Diabetologia 1999, 42:1383-1394.
• [24]Ding SS, Qiu C, Hess P, Xi JF, Zheng N, Clozel M: Chronic endothelin receptor blockade prevents both early hyperfiltration and late overt diabetic nephropathy in the rat. J Cardiovasc Pharmacol 2003, 42:48-54.
• [25]Saleh MA, Boesen EI, Pollock JS, Savin VJ, Pllock DM: Endothelin receptor A-specific stimulation of glomerular inflammation and injury in a streptozocin-induced rat model of diabetes. Diabetologia 2011, 54:979-988.
• [26]Barton M: Therapeutic potential of endothelin receptor antagonists for chronic proteinuric renal disease in humans. Biochem Biophys Acta 2010, 1802:1203-1213.
• [27]Mann JF, Green D, Jamerson K, et al.: Avosentan for overt diabetic nephropathy. J Am Soc Nephrol 2010, 21:527-535.
• [28]Kankova K, Stejskalova A, Pacal L, Tschoplova S, Hertlova M, Krusova D, et al.: Genetic risk factors for diabetic nephropathy on chromosomes 6p and 7q identified by the set-association approach. Diabetologia 2007, 50:990-999.
• [29]Manea SA, Robciuc A, Guja C, Heltianu C: Identification of gene variants in NOS3, ET-1 and RAS that confer risk and protection against microangiopathy in type 2 diabetic obese subjects. Biochem Biophys Res Commun. 2011, 407(3):486-490.
• [30]Asai T, Ohkubo T, Katsuya T, Higaki J, Fu Y, Fukuda M, et al.: Endothelin-1 gene variant associates with blood pressure in obese Japanese subjects: the Ohasama Study. Hypertension 2001, 38:1321-1324.
• [31]Jin JJ, Nakura J, Wu Z, Yamamoto M, Abe M, Tabara Y, et al.: Association of endothelin-1 gene variant with hypertension. Hypertension 2003, 41:163-167.
• [32]Treiber FA, Barbeau P, Harshfield G, Kang HS, Pollock DM, Pollock JS, et al.: Endothelin-1 gene Lys198Asn polymorphism and blood pressure reactivity. Hypertension 2003, 42:494-499.
• [33]Pare G, Serre D, Brisson D, Anand SS, Montpetit A, Tremblay G, et al.: Genetic analysis of 103 candidate genes for coronary artery disease and associated phenotypes in a founder population reveals a new association between endothelin-1 and high-density lipoprotein cholesterol. Am J Hum Genet 2007, 80:673-682.
• [34]Li H, Louey JW, Choy KW, Liu DT, Chan WM, Chan YM, et al.: Lys198Asn is associated with diabetic retinopathy in type 2 diabetes. Mol Vis 1008, 14:1698-1704.
• [35]Barden AE, Herbison CE, Beilin LJ, Michael CA, Walters BN, Van Bockxmeer FM: Association between the endothelin-1 gene Lys198Asn polymorphism blood pressure and plasma endothelin-1 levels in normal and pre-eclamptic pregnancy. J Hypertens 2001, 19:1775-1782.
• [36]Tanaka C, Kamide K, Takiuchi S, Kawano Y, Miyata T: Evaluation of the Lys198Asn and -134delA genetic polymorphisms of the endothelin-1 gene. Hypertens Res 2004, 27:367-371.