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Synergistical action of the β2 adrenoceptor and fatty acid binding protein 2 polymorphisms on the loss of glomerular filtration rate in Chinese patients with type 2 diabetic nephropathy

  • Nephrology - Original Paper
  • Published:
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Abstract

Purpose

Since altered sympathetic nerve activity and insulin resistance are implicated in the pathogenesis of type 2 diabetic nephropathy, we investigated the effect of polymorphic Arg16Gly and Gln27Glu in the β2 adrenoceptor gene and Ala54Thr in the fatty acid binding protein 2 gene on the estimated glomerular filtration rate (eGFR) in Chinese patients with the above disease.

Methods

A total of 552 diabetic subjects recruited from annual health examinations were studied. The eGFR was calculated from the Modification of Diet in Renal Disease equation for the Chinese. Plasma norepinephrine level and genotype were determined by high-performance liquid chromatography–tandem mass spectrometry and TaqMan method, respectively. Holter-derived heart rate viability (HRV) and the MRI-generated renal apparent diffusion coefficient (ADC) were evaluated.

Results

The Gly16Gly and Thr54Thr homozygotes had significantly higher microalbuminuria and lower eGFR against other genotypes in their individual polymorphism. Besides, the Gly16Gly variant exhibited markedly elevated norepinephrine level, whereas indicative of insulin resistance was increased in the Thr54Thr one. Multiple linear regression analysis further confirmed the independent genetic effect on the eGFR. Moreover, multifactor dimensionality reduction method detected a gene–gene synergistic action that subjects with the Gly16Gly/Thr54Thr genotype were exposed to higher risk of eGFR loss. Finally, these findings were accompanied by lower HRV and ADC, indicating sympathetically mediated hemodynamic changes.

Conclusions

By uncovering the genetic component of the coherent interplay between the elevated sympathetic nerve activity and metabolic disorders, our observations might promote the development of novel personalized prevention and management strategies against the diabetic nephropathy, especially in the genetically susceptible individuals.

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References

  1. Nakagawa T, Tanabe K, Croker BP, Johnson RJ, Grant MB, Kosugi T, Li QH (2011) Endothelial dysfunction as a potential contributor in diabetic nephropathy. Nat Rev Nephrol 7(1):36–44. https://doi.org/10.1038/nrneph.2010.152

    Article  PubMed  Google Scholar 

  2. Coccheri S (2007) Approaches to prevention of cardiovascular complications and events in diabetes mellitus. Drugs 67(7):997–1026. https://doi.org/10.2165/00003495-200767070-00005

    Article  CAS  PubMed  Google Scholar 

  3. Joles JA, Koomans HA (2004) Causes and consequences of increased sympathetic activity in renal disease. Hypertension 43(4):699–706. https://doi.org/10.1161/01.HYP.0000121881.77212.b1

    Article  CAS  PubMed  Google Scholar 

  4. Hall JE, Jones DW, Kuo JJ, da Silva A, Tallam LS, Liu J (2003) Impact of the obesity epidemic on hypertension and renal disease. Curr Hypertens Rep 5(5):386–392. https://doi.org/10.1007/s11906-003-0084-z

    Article  PubMed  Google Scholar 

  5. Esler M, Rumantir M, Wisener G, Kaye D, Lambert G, Hasting J (2001) Sympathetic nervous system and insulin resistance from obesity to diabetes. Am J Hyperten 14(11–2):304S–309S. https://doi.org/10.1016/S0895-7061(01)02236-1

    Article  CAS  Google Scholar 

  6. Lindner D, Wanner MC, Berger M (2003) Genetic aspects of diabetic nephropathy. Kidney Int Suppl 63(84):S186–S1913. https://doi.org/10.1046/j.1523-1755.63.s84.24.x

    Article  Google Scholar 

  7. Freedman BI, Bostrom M, Daeihagh P, Bowden DW (2007) Genetic factors in diabetic nephropathy. Clin J Am Soc Nephrol 2(6):1306–1316. https://doi.org/10.2215/CJN.02560607

    Article  CAS  PubMed  Google Scholar 

  8. Chen Y, Lipkowitz MS, Salem RM, Fung MM, Bhatnagar V, Mahata M, Nievergelt CM, Rao F, Mahata SK, Schork NJ, Hicks PJ, Bowden DW, Freedman BI, Brophy VH, O’Connor DT, AASK (2010) Progression of chronic kidney disease: adrenergic genetic influence on glomerular filtration rate decline in hypertensive nephrosclerosis. Am J Nephrol 32(1):23–30. https://doi.org/10.1159/000313927

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Canani LH, Capp C, Ng DP, Choo SG, Maia AL, Nabinger GB, Santos K, Crispim D, Roisemberg I, Krolewski AS, Gross JL (2005) The fatty acid-binding protein-2 A54T polymorphism is associated with renal disease in patients with type 2 diabetes. Diabetes 54(11):3326–3330. https://doi.org/10.2337/diabetes.54.11.3326

    Article  CAS  PubMed  Google Scholar 

  10. Leineweber K, Heusch G (2009) β1- and β2-adrenoceptor polymorphisms and cardiovascular diseases. Br J Pharmacol 58(1):61–69. https://doi.org/10.1111/j.1476-5381.2009.00187.x

    Article  Google Scholar 

  11. Masuo K, Katsuya T, Sugimoto K, Kawaguchi H, Rakugi H, Ogihara T, Tuck ML (2007) High plasma norepinephrine levels associated with beta2-adrenoceptor polymorphisms predict future renal damage in nonobese normotensive individuals. Hypertens Res 30(6):503–511. https://doi.org/10.1291/hypres.30.503

    Article  CAS  PubMed  Google Scholar 

  12. Weiss EP, Brown MD, Shuldiner AR, Hagberg JM (2002) Fatty acid binding protein-2 gene variants and insulin resistance: gene and gene-environment interaction effects. Physiol Genomics 10(3):145–157. https://doi.org/10.1152/physiolgenomics.00070.2001

    Article  CAS  PubMed  Google Scholar 

  13. Yoshida T, Kato K, Yokoi K, Watanabe S, Metoki N, Yoshida H, Satoh K, Aoyagi Y, Nishigaki Y, Suzuki T, Nozawa Y, Yamada Y (2009) Association of genetic variants with chronic kidney disease in Japanese individuals with type 2 diabetes mellitus. Int J Mol Med 23(4):529–537. https://doi.org/10.3892/ijmm_00000161

    CAS  PubMed  Google Scholar 

  14. Marti A, Martinez-González MA, Martinez JA (2008) Interaction between genes and lifestyle factors on obesity. Proc Nutr Soc 67(1):1–8. https://doi.org/10.1111/j.1365-3032.2003.00340.x

    Article  CAS  PubMed  Google Scholar 

  15. Wang T, Karino K, Yamasaki M, Zhang Y, Masuda J, Yamaguchi S, Shiwaku K, Nabika T (2009) Effects of G994T in the Lp-PLA2 gene on the plasma oxidized LDL level and carotid intima-media thickness in Japanese—the Shimane Study. Am J Hypertens 22(7):742–747. https://doi.org/10.1038/ajh.2009.70

    Article  CAS  PubMed  Google Scholar 

  16. Masuo K, Kawaguchi H, Mikami H, Ogihara T, Tuck ML (2003) Serum uric acid and plasma norepinephrine concentrations predict subsequent weight gain and blood pressure elevation. Hypertension 42(4):474–480. https://doi.org/10.1161/01.HYP.0000091371.53502.D3

    Article  CAS  PubMed  Google Scholar 

  17. Ma YC, Zuo L, Chen JH, Luo Q, Yu XQ, Li Y, Xu JS, Huang SM, Wang LN, Huang W, Wang M, Xu GB, Wang HY (2006) Modified glomerular filtration rate estimating equation for Chinese patients with chronic kidney disease. J Am Soc Nephrol 17:2927–2944. https://doi.org/10.1681/ASN.2006040368

    Article  Google Scholar 

  18. Kudat H, Akkaya V, Sozen AB, Salman S, Demirel S, Ozcan M, Atilgan D, Yilmaz MT, Guven O (2006) Heart rate variability in diabetes patients. J Int Med Res 34(3):291–296. https://doi.org/10.1177/147323000603400308

    Article  CAS  PubMed  Google Scholar 

  19. Cakmak P, Yağcı AB, Dursun B, Herek D, Fenkçi SM (2014) Renal diffusion-weighted imaging in diabetic nephropathy: correlation with clinical stages of disease. Diagn Interv Radiol 20(5):374–378. https://doi.org/10.5152/dir.2014.13513

    Article  PubMed  PubMed Central  Google Scholar 

  20. Wang T, Zhang Y, Ma J, Feng Z, Niu K, Liu B (2014) Additive effect of polymorphisms in the β2-adrenoceptor and NADPH oxidase p22phox genes contributes to the loss of estimated glomerular filtration rate in Chinese. Clin Exp Pharmacol Physiol 41(9):657–662. https://doi.org/10.1111/1440-1681.12268

    CAS  PubMed  Google Scholar 

  21. Van Eenoo P, Delbeke FT (2010) Beta-adrenergic stimulation. Handb Exp Pharmacol 195:227–249. https://doi.org/10.1007/978-3-540-79088-4_11

    Article  Google Scholar 

  22. Göthert M, Hentrich F (1985) Identification of presynaptic beta 2-adrenoceptors on the sympathetic nerve fibres of the human pulmonary artery. Br J Pharmacol 85(4):933–941

    Article  PubMed  PubMed Central  Google Scholar 

  23. Francis GS (1988) Modulation of peripheral sympathetic nerve transmission. J Am Coll Cardiol 12(1):250–254. https://doi.org/10.1016/0735-1097(88)90382-8

    Article  CAS  PubMed  Google Scholar 

  24. Dorn GW 2nd (2010) Adrenergic signaling polymorphisms and their impact on cardiovascular disease. Physiol Rev 90(3):1013–1062. https://doi.org/10.1152/physrev.00001.2010

    Article  CAS  PubMed  Google Scholar 

  25. Atala MM, Goulart A, Guerra GM, Mostarda C, Rodrigues B, Mello PR, Casarine DE, Irigoyen MC, Pereira AC, Consolim-Colombo FM (2015) Arg16Gly and Gln27Glu β2 adrenergic polymorphisms influence cardiac autonomic modulation and baroreflex sensitivity in healthy young Brazilians. Am J Transl Res 7(1):153–161

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Nashar K, Egan BM (2014) Relationship between chronic kidney disease and metabolic syndrome: current perspectives. Diabetes Metab Syndr Obes 7:421–435. https://doi.org/10.2147/DMSO.S45183

    Article  PubMed  PubMed Central  Google Scholar 

  27. Masuo K, Rakugi H, Ogihara T, Esler MD, Lambert GW (2010) Cardiovascular and renal complications of type 2 diabetes in obesity: role of sympathetic nerve activity and insulin resistance. Curr Diabetes Rev 6(2):58–67. https://doi.org/10.2174/157339910790909396

    Article  CAS  PubMed  Google Scholar 

  28. Ritchie MD, Hahn LW, Roodi N, Bailey LR, Dupont WD, Parl FF, Moore JH (2001) Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer. Am J Hum Genet 69(1):138–147. https://doi.org/10.1086/321276

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Sinski M, Lewandowski J, Abramczyk P, Narkiewicz K, Gaciong Z (2006) Why study sympathetic nervous system? J Physiol Pharmacol 57(Suppl 11):79–92

    PubMed  Google Scholar 

  30. Wang T, Nabika T, Notsu Y, Takabatake T (2008) Sympathetic regulation of renal functions in the SHRSP-based congenic rats for chromosome-1 blood pressure QTL. Hypertens Res 31(3):561–568. https://doi.org/10.1291/hypres.31.561

    Article  CAS  PubMed  Google Scholar 

  31. Wang T, Takabatake T, Kobayashi Y, Nabika T (2008) Sympathetic regulation of the renal functions in the reciprocal congenic rats for chromosome 1 blood pressure QTL. Clin Exp Pharmacol Physiol 35(11):1365–1370. https://doi.org/10.1111/j.1440-1681.2008.04990.x

    Article  CAS  PubMed  Google Scholar 

  32. Najafian B, Mauer M (2012) Morphological features of declining renal function in type 1 diabetes. Semin Nephrol 32(5):415–422. https://doi.org/10.1016/j.semnephrol.2012.07

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank Eric J. Gayetsky (Dublin, OH, USA) for English language editing and. Dr. HongYu Geng for the data collection especially the HRV.

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Authors and Affiliations

  1. Department of Nephrology, HeBei General Hospital, No. 348 West HePing Boulevard, Shijiazhuang, 050051, People’s Republic of China

    Tao Wang, Qiong Liu, ZeKai Wang, Bing Liu & Kai Niu

  2. Department of Dermatology, The 4th Affiliated Hospital of HeBei Medical University, No. 12 JianKang Road, Shijiazhuang, 050011, People’s Republic of China

    Yan Zhang

  3. Department of Radiology, The 4th Affiliated Hospital of HeBei Medical University, No. 12 JianKang Road, Shijiazhuang, 050011, People’s Republic of China

    Ning Wang

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  1. Tao Wang
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Correspondence to Tao Wang.

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Wang, T., Zhang, Y., Wang, N. et al. Synergistical action of the β2 adrenoceptor and fatty acid binding protein 2 polymorphisms on the loss of glomerular filtration rate in Chinese patients with type 2 diabetic nephropathy. Int Urol Nephrol 50, 715–723 (2018). https://doi.org/10.1007/s11255-018-1812-2

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