Clinical and Experimental Nephrology

, Volume 22, Issue 4, pp 764–772 | Cite as

The functionality of African-specific variants in the TGFB1 regulatory region and their potential role in HIVAN

  • M. Nel
  • J.-M. Buys
  • F. C. J. Botha
  • N. Wearne
  • S. Prince
  • J. M. HeckmannEmail author
Original article



Transcription of transforming growth factor beta-1 (TGF-β1) is regulated by a polymorphic promoter region containing African-specific single nucleotide polymorphisms (SNPs). Some of these SNPs have higher frequencies among Southern Africans compared to other African populations and their functionality has only been partially studied. Due to the high prevalence of HIV-associated nephropathy (HIVAN) in Africans we hypothesized that functional African TGFB1-promoter SNPs may contribute to HIVAN pathogenesis.


The functionality of the TGFB1 -1347 C>T variant and African-specific variants (-1287 G>A, -1154 C>T, -387 C>T and -14 G>A) were examined by measuring reporter gene expression in kidney and fibroblast cell lines co-transfected with TGFB1-promoter constructs and an HIV-Tat expression vector. TGF-β1 immunohistochemical staining was performed on kidney biopsies with HIVAN (n = 18) and compared to control biopsies without HIVAN or tubulointerstitial disease (n = 12) using semi-quantitative and digital image analysis. HIVAN cases were genotyped for TGFB1 -1347 and -387 SNP variants.


TGFB1-promoter haplotypes containing the African -387 T-allele resulted in ~ five-fold repression of TGFB1-promoter activity compared to -387 C haplotypes (p ≤ 0.024). HIV-Tat upregulated TGFB1-promoter activity for haplotypes containing -1347 T and -387 T in transfected renal cells (≈ 1.6-fold; p ≤ 0.030) and fibroblasts (≈ 1.3-fold; p ≤ 0.016). The renal interstitium from HIVAN biopsies, compared to HIV-positive and -negative controls, differed in the semi-quantitative TGF-β1 staining and digital optical density analyses. The TGFB1 -1347 and -387 genotypes in HIVAN cases were similar to population controls.


African-specific haplotypes lower TGFB1-promoter activity and expression levels and HIV-Tat upregulates TGFB1 promoter activity irrespective of the haplotype.


Transforming growth factor B1 Promoter Polymorphism HIVAN Kidney Africa 



The authors wish to thank Professor Mitra (National Center for Cell Sciences, India) who kindly donated the plasmid pcDNA-Tat, Mrs. Padmini Govender (Division of Anatomical Pathology, University of Cape Town) for assistance with the immunohistochemical staining. In addition, a special thanks to Ms Susan Cooper and Prof DM Lang for their technical assistance with the digital image analysis (Confocal & Light Microscope Imaging Facility, University of Cape Town). J-MB and SP received funding from the South African National Research foundation (NRF), MN from the UCT Neurology fund, and JMH and NW from the South African Medical Research Council.

Compliance with ethical standards

Conflict of interest

The authors have declared that no conflict of interest exists.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the University of Cape Town’s Health Sciences Faculty institutional research committee at which the studies were conducted (HREC 491/2008) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Supplementary material

10157_2017_1516_MOESM1_ESM.docx (30 kb)
Supplementary material 1 (DOCX 30 KB)


  1. 1.
    Yoshioka K, Takemura T, Murakami K, Okada M, Hino S, Miyamoto H, Maki S. Transforming growth factor-beta protein and mRNA in glomeruli in normal and diseased human kidneys. Lab Invest. 1993;68(2):154–163.PubMedGoogle Scholar
  2. 2.
    Yamamoto T, Noble NA, Cohen AH, Nast CC, Hishida A, Gold LI, Border WA. Expression of transforming growth factor-beta isoforms in human glomerular diseases. Kidney Int. 1996;49(2):461–9.CrossRefPubMedGoogle Scholar
  3. 3.
    Massague J, Seoane J, Wotton D. Smad transcription factors. Genes Dev. 2005;19(23):2783–10.CrossRefPubMedGoogle Scholar
  4. 4.
    Border WA, Noble NA. Transforming growth factor-beta in glomerular injury. Exp Nephrol. 1994;2(1):13 – 7.PubMedGoogle Scholar
  5. 5.
    Eddy AA. Overview of the cellular and molecular basis of kidney fibrosis. Kidney Int Suppl. 2011;4(1):2–8. 2014.CrossRefGoogle Scholar
  6. 6.
    Shah R, Rahaman B, Hurley CK, Posch PE. Allelic diversity in the TGFB1 regulatory region: characterization of novel functional single nucleotide polymorphisms. Hum Genet. 2006;119(1–2):61–74.CrossRefPubMedGoogle Scholar
  7. 7.
    Nel M, Buys JM, Rautenbach R, Mowla S, Prince S, Heckmann JM. The African-387 C > T TGFB1 variant is functional and associates with the ophthalmoplegic complication in juvenile myasthenia gravis. J Hum Genet 2016;61(4):307–316.CrossRefPubMedGoogle Scholar
  8. 8.
    Hu BC, Chu SL, Wang GL, Gao PJ, Zhu DL, Wang JG. Association between genetic variation in transforming growth factors beta1 and beta3 and renal dysfunction in non-diabetic Chinese. Clin Exp Hypertens. 2008;30(2):121–31.CrossRefPubMedGoogle Scholar
  9. 9.
    Brezzi B, Del Prete D, Lupo A, Magistroni R, Gomez-Lira M, Bernich P, et al. Primary IgA nephropathy is more severe in TGF-beta1 high secretor patients. J Nephrol. 2009;22(6):747 – 59.PubMedGoogle Scholar
  10. 10.
    Zaffanello M, Tardivo S, Cataldi L, Fanos V, Biban P, Malerba G. Genetic susceptibility to renal scar formation after urinary tract infection: a systematic review and meta-analysis of candidate gene polymorphisms. Pediatr Nephrol. 2011;26(7):1017–29.CrossRefPubMedGoogle Scholar
  11. 11.
    Nikolova PN, Ivanova MI, Mihailova SM, Myhailova AP, Baltadjieva DN, Simeonov PL, et al. Cytokine gene polymorphism in kidney transplantation–impact of TGF-beta 1, TNF-alpha and IL-6 on graft outcome. Transpl Immunol. 2008;18(4):344–8.CrossRefPubMedGoogle Scholar
  12. 12.
    Kiryluk K, Martino J, Gharavi AG. Genetic susceptibility, HIV infection, and the kidney. Clin J Am Soc Nephrol. 2007;2(Suppl 1):S25–35.CrossRefPubMedGoogle Scholar
  13. 13.
    Gerntholtz TE, Goetsch SJ, Katz I. HIV-related nephropathy: a South African perspective. Kidney Int. 2006;69(10):1885–91.CrossRefPubMedGoogle Scholar
  14. 14.
    Friedman DJ, Pollak MR. Genetics of kidney failure and the evolving story of APOL1. J Clin Invest. 2011;121(9):3367–74.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Kasembeli AN, Duarte R, Ramsay M, Naicker S. African origins and chronic kidney disease susceptibility in the human immunodeficiency virus era. World J Nephrol. 2015;4(2):295–306.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Bodi I, Kimmel PL, Abraham AA, Svetkey LP, Klotman PE, Kopp JB. Renal TGF-beta in HIV-associated kidney diseases. Kidney Int. 1997;51(5):1568–77.CrossRefPubMedGoogle Scholar
  17. 17.
    Cohen AH, Nast CC. HIV-associated nephropathy. A unique combined glomerular, tubular, and interstitial lesion. Mod Pathol. 1988;1(2):87–97.PubMedGoogle Scholar
  18. 18.
    Yamamoto T, Noble NA, Miller DE, Gold LI, Hishida A, Nagase M, et al. Increased levels of transforming growth factor-beta in HIV-associated nephropathy. Kidney Int. 1999;55(2):579–592.CrossRefPubMedGoogle Scholar
  19. 19.
    Thatikunta P, Sawaya BE, Denisova L, Cole C, Yusibova G, Johnson EM, et al. Identification of a cellular protein that binds to Tat-responsive element of TGF beta-1 promoter in glial cells. J Cell Biochem. 1997;67(4):466–477.CrossRefPubMedGoogle Scholar
  20. 20.
    Joseph AM, Ladha JS, Mojamdar M, Mitra D. Human immunodeficiency virus-1 Nef protein interacts with Tat and enhances HIV-1 gene expression. FEBS Lett. 2003;548(1–3):37–42.CrossRefPubMedGoogle Scholar
  21. 21.
    Genovese G, Friedman DJ, Ross MD, Lecordier L, Uzureau P, Freedman BI, et al. Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science. 2010;329(5993):841–845.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Wearne N, Swanepoel CR, Boulle A, Duffield MS, Rayner BL. The spectrum of renal histologies seen in HIV with outcomes, prognostic indicators and clinical correlations. Nephrol Dial Transplant. 2012;27(11):4109–4118.CrossRefPubMedGoogle Scholar
  23. 23.
    Fedchenko N, Reifenrath J. Different approaches for interpretation and reporting of immunohistochemistry analysis results in the bone tissue—a review. Diagn Pathol. 2014;9:221.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    May A, Hazelhurst S, Li Y, Norris SA, Govind N, Tikly M, Hon C, et al. Genetic diversity in black South Africans from Soweto. BMC Genom. 2013;14:644.CrossRefGoogle Scholar
  25. 25.
    Loregian A, Bortolozzo K, Boso S, Caputo A, Palu G. Interaction of Sp1 transcription factor with HIV-1 Tat protein: looking for cellular partners. FEBS Lett. 2003;543(1–3):61–65.CrossRefPubMedGoogle Scholar
  26. 26.
    Bettaccini AA, Baj A, Accolla RS, Basolo F, Toniolo AQ. Proliferative activity of extracellular HIV-1 Tat protein in human epithelial cells: expression profile of pathogenetically relevant genes. BMC Microbiol. 2005;5:20.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Rizzardi AE, Johnson AT, Vogel RI, Pambuccian SE, Henriksen J, Skubitz AP, et al. Quantitative comparison of immunohistochemical staining measured by digital image analysis versus pathologist visual scoring. Diagn Pathol. 2012;7:42.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Diana NE, Naicker S. Update on current management of chronic kidney disease in patients with HIV infection. Int J Nephrol Renovasc Dis. 2016;9:223 – 34.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Han TM, Naicker S, Ramdial PK, Assounga AG. A cross-sectional study of HIV-seropositive patients with varying degrees of proteinuria in South Africa. Kidney Int. 2006;69(12):2243–50.CrossRefPubMedGoogle Scholar

Copyright information

© Japanese Society of Nephrology 2017

Authors and Affiliations

  1. 1.Neurology Research Group, Division of Neurology, Department of MedicineUniversity of Cape TownCape TownSouth Africa
  2. 2.Division of Anatomical Pathology, Department of PathologyUniversity of Cape TownCape TownSouth Africa
  3. 3.Division of Nephrology, Department of MedicineUniversity of Cape TownCape TownSouth Africa
  4. 4.Division of Cell Biology, Department of Human BiologyUniversity of Cape TownCape TownSouth Africa
  5. 5.Division of NeurologyDepartment of Medicine, Groote Schuur HospitalCape TownSouth Africa

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