APOL1-G0 protects podocytes in a mouse model of HIV-associated nephropathy

Autoři: Leslie A. Bruggeman aff001;  Zhenzhen Wu aff001;  Liping Luo aff001;  Sethu Madhavan aff003;  Paul E. Drawz aff004;  David B. Thomas aff005;  Laura Barisoni aff006;  John F. O'Toole aff001;  John R. Sedor aff001
Působiště autorů: Departments of Inflammation & Immunity and Nephrology, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America aff001;  Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America aff002;  Department of Medicine, Ohio State University, Columbus, Ohio, United States of America aff003;  Department of Medicine, University of Minnesota, Minneapolis, Minnesota, United States of America aff004;  Departments of Pathology, University of Miami, Miami, Florida, United States of America aff005;  Departments of Pathology and Medicine, Duke University, Durham, North Carolina, United States of America aff006
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: 10.1371/journal.pone.0224408


African polymorphisms in the gene for Apolipoprotein L1 (APOL1) confer a survival advantage against lethal trypanosomiasis but also an increased risk for several chronic kidney diseases (CKD) including HIV-associated nephropathy (HIVAN). APOL1 is expressed in renal cells, however, the pathogenic events that lead to renal cell damage and kidney disease are not fully understood. The podocyte function of APOL1-G0 versus APOL1-G2 in the setting of a known disease stressor was assessed using transgenic mouse models. Transgene expression, survival, renal pathology and function, and podocyte density were assessed in an intercross of a mouse model of HIVAN (Tg26) with two mouse models that express either APOL1-G0 or APOL1-G2 in podocytes. Mice that expressed HIV genes developed heavy proteinuria and glomerulosclerosis, and had significant losses in podocyte numbers and reductions in podocyte densities. Mice that co-expressed APOL1-G0 and HIV had preserved podocyte numbers and densities, with fewer morphologic manifestations typical of HIVAN pathology. Podocyte losses and pathology in mice co-expressing APOL1-G2 and HIV were not significantly different from mice expressing only HIV. Podocyte hypertrophy, a known compensatory event to stress, was increased in the mice co-expressing HIV and APOL1-G0, but absent in the mice co-expressing HIV and APOL1-G2. Mortality and renal function tests were not significantly different between groups. APOL1-G0 expressed in podocytes may have a protective function against podocyte loss or injury when exposed to an environmental stressor. This was absent with APOL1-G2 expression, suggesting APOL1-G2 may have lost this protective function.

Klíčová slova:

Glomeruli – HIV – Chronic kidney disease – Kidneys – Mouse models – Renal system – Animal models of disease – Genetically modified animals


1. 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. doi: 10.1126/science.1193032 20647424

2. Kasembeli AN, Duarte R, Ramsay M, Mosiane P, Dickens C, Dix-Peek T, et al. APOL1 Risk Variants Are Strongly Associated with HIV-Associated Nephropathy in Black South Africans. J Am Soc Nephrol. 2015;26(11):2882–2890. doi: 10.1681/ASN.2014050469 25788523

3. Kopp JB, Nelson GW, Sampath K, Johnson RC, Genovese G, An P, et al. APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy. J Am Soc Nephrol. 2011;22(11):2129–2137. doi: 10.1681/ASN.2011040388 21997394

4. Lipkowitz MS, Freedman BI, Langefeld CD, Comeau ME, Bowden DW, Kao WH, et al. Apolipoprotein L1 gene variants associate with hypertension-attributed nephropathy and the rate of kidney function decline in African Americans. Kidney Int. 2013;83(1):114–120. doi: 10.1038/ki.2012.263 22832513

5. Tzur S, Rosset S, Shemer R, Yudkovsky G, Selig S, Tarekegn A, et al. Missense mutations in the APOL1 gene are highly associated with end stage kidney disease risk previously attributed to the MYH9 gene. Hum Genet. 2010;128(3):345–350. doi: 10.1007/s00439-010-0861-0 20635188

6. Kruzel-Davila E, Wasser WG, Skorecki K. APOL1 Nephropathy: A Population Genetics and Evolutionary Medicine Detective Story. Sem Nephrol. 2017;37(6):490–507.

7. Bruggeman LA, O'Toole JF, Ross MD, Madhavan SM, Smurzynski M, Wu K, et al. Plasma apolipoprotein L1 levels do not correlate with CKD. J Am Soc Nephrol. 2014;25(3):634–644. doi: 10.1681/ASN.2013070700 24231663

8. Kozlitina J, Zhou H, Brown PN, Rohm RJ, Pan Y, Ayanoglu G, et al. Plasma Levels of Risk-Variant APOL1 Do Not Associate with Renal Disease in a Population-Based Cohort. J Am Soc Nephrol. 2016;27(10):3204–3219. doi: 10.1681/ASN.2015101121 27005919

9. Freedman BI, Julian BA, Pastan SO, Israni AK, Schladt D, Gautreaux MD, et al. Apolipoprotein L1 gene variants in deceased organ donors are associated with renal allograft failure. Am J Transplant. 2015;15(6):1615–1622. doi: 10.1111/ajt.13223 25809272

10. Lee BT, Kumar V, Williams TA, Abdi R, Bernhardy A, Dyer C, et al. The APOL1 genotype of African American kidney transplant recipients does not impact 5-year allograft survival. Am J Transplant. 2012;12(7):1924–1928. doi: 10.1111/j.1600-6143.2012.04033.x 22487534

11. Reeves-Daniel AM, DePalma JA, Bleyer AJ, Rocco MV, Murea M, Adams PL, et al. The APOL1 gene and allograft survival after kidney transplantation. Am J Transplant. 2011;11(5):1025–1030. doi: 10.1111/j.1600-6143.2011.03513.x 21486385

12. Ma L, Shelness GS, Snipes JA, Murea M, Antinozzi PA, Cheng D, et al. Localization of APOL1 protein and mRNA in the human kidney: nondiseased tissue, primary cells, and immortalized cell lines. J Am Soc Nephrol. 2015;26(2):339–348. doi: 10.1681/ASN.2013091017 25012173

13. Madhavan SM, O'Toole JF, Konieczkowski M, Barisoni L, Thomas DB, Ganesan S, et al. APOL1 variants change C-terminal conformational dynamics and binding to SNARE protein VAMP8. JCI Insight. 2017;2(14) pii: 92581. doi: 10.1172/jci.insight.92581 28724794

14. Madhavan SM, O'Toole JF, Konieczkowski M, Ganesan S, Bruggeman LA, Sedor JR. APOL1 localization in normal kidney and nondiabetic kidney disease. J Am Soc Nephrol. 2011;22(11):2119–2128. doi: 10.1681/ASN.2011010069 21997392

15. Marras D, Bruggeman LA, Gao F, Tanji N, Mansukhani MM, Cara A, et al. Replication and compartmentalization of HIV-1 in kidney epithelium of patients with HIV-associated nephropathy. Nat Med. 2002;8(5):522–526. doi: 10.1038/nm0502-522 11984599

16. Bruggeman LA, Dikman S, Meng C, Quaggin SE, Coffman TM, Klotman PE. Nephropathy in human immunodeficiency virus-1 transgenic mice is due to renal transgene expression. J Clin Invest. 1997;100(1):84–92. doi: 10.1172/JCI119525 9202060

17. Bruggeman LA, Ross MD, Tanji N, Cara A, Dikman S, Gordon RE, et al. Renal epithelium is a previously unrecognized site of HIV-1 infection. J Am Soc Nephrol. 2000;11(11):2079–2087. 11053484

18. Canaud G, Dejucq-Rainsford N, Avettand-Fenoel V, Viard JP, Anglicheau D, Bienaime F, et al. The kidney as a reservoir for HIV-1 after renal transplantation. J Am Soc Nephrol. 2014;25(2):407–419. doi: 10.1681/ASN.2013050564 24309185

19. Cohen AH, Sun NC, Shapshak P, Imagawa DT. Demonstration of human immunodeficiency virus in renal epithelium in HIV-associated nephropathy. Mod Pathol. 1989;2(2):125–128. 2657719

20. Jolicoeur P, Kay DG, Cool M, Jothy S, Rebai N, Hanna Z. A novel mouse model of HIV-1 disease. Leukemia. 1999;13 Suppl 1:S78–80.

21. Kimmel PL, Ferreira-Centeno A, Farkas-Szallasi T, Abraham AA, Garrett CT. Viral DNA in microdissected renal biopsy tissue from HIV infected patients with nephrotic syndrome. Kidney Int. 1993;43(6):1347–1352. doi: 10.1038/ki.1993.189 8315949

22. Winston JA, Bruggeman LA, Ross MD, Jacobson J, Ross L, D'Agati VD, et al. Nephropathy and establishment of a renal reservoir of HIV type 1 during primary infection. N Engl J Med. 2001;344(26):1979–1984. doi: 10.1056/NEJM200106283442604 11430327

23. Zhong J, Zuo Y, Ma J, Fogo AB, Jolicoeur P, Ichikawa I, et al. Expression of HIV-1 genes in podocytes alone can lead to the full spectrum of HIV-1-associated nephropathy. Kidney Int. 2005;68(3):1048–1060. doi: 10.1111/j.1523-1755.2005.00497.x 16105035

24. Zuo Y, Matsusaka T, Zhong J, Ma J, Ma LJ, Hanna Z, et al. HIV-1 genes vpr and nef synergistically damage podocytes, leading to glomerulosclerosis. J Am Soc Nephrol. 2006;17(10):2832–2843. doi: 10.1681/ASN.2005080878 16988066

25. Bruggeman LA, Wu Z, Luo L, Madhavan SM, Konieczkowski M, Drawz PE, et al. APOL1-G0 or APOL1-G2 Transgenic models eevelop preeclampsia but not kidney disease. J Am Soc Nephrol. 2016;27(12):3600–3610. doi: 10.1681/ASN.2015111220 27026370

26. Kopp JB, Klotman ME, Adler SH, Bruggeman LA, Dickie P, Marinos NJ, et al. Progressive glomerulosclerosis and enhanced renal accumulation of basement membrane components in mice transgenic for human immunodeficiency virus type 1 genes. Proc Natl Acad Sci (USA). 1992;89(5):1577–1581.

27. Prakash S, Papeta N, Sterken R, Zheng Z, Thomas RL, Wu Z, et al. Identification of the nephropathy-susceptibility locus HIVAN4. J Am Soc Nephrol. 2011;22(8):1497–1504. doi: 10.1681/ASN.2011020209 21784893

28. Venkatareddy M, Wang S, Yang Y, Patel S, Wickman L, Nishizono R, et al. Estimating podocyte number and density using a single histologic section. J Am Soc Nephrol. 2014;25(5):1118–1129. doi: 10.1681/ASN.2013080859 24357669

29. Gharavi AG, Ahmad T, Wong RD, Hooshyar R, Vaughn J, Oller S, et al. Mapping a locus for susceptibility to HIV-1-associated nephropathy to mouse chromosome 3. Proc Natl Acad Sci (USA) 2004;101(8):2488–2493.

30. Kikuchi M, Wickman L, Hodgin JB, Wiggins RC. Podometrics as a potential clinical tool for glomerular disease management. Sem Nephrol. 2015;35(3):245–255.

31. O'Toole JF, Bruggeman LA, Madhavan S, Sedor JR. The Cell Biology of APOL1. Semin Nephrol. 2017;37(6):538–545. doi: 10.1016/j.semnephrol.2017.07.007 29110761

32. Barisoni L, Bruggeman LA, Mundel P, D'Agati VD, Klotman PE. HIV-1 induces renal epithelial dedifferentiation in a transgenic model of HIV-associated nephropathy. Kidney Int. 2000;58(1):173–181. doi: 10.1046/j.1523-1755.2000.00152.x 10886562

33. Rosenstiel P, Gharavi A, D'Agati V, Klotman P. Transgenic and infectious animal models of HIV-associated nephropathy. J Am Soc Nephrol. 2009;20(11):2296–2304 doi: 10.1681/ASN.2008121230 19497967

34. Kriz W. Glomerular diseases: podocyte hypertrophy mismatch and glomerular disease. Nat Rev Nephrol. 2012;8(11):618–9. doi: 10.1038/nrneph.2012.198 23007616

35. Fukuda A, Chowdhury MA, Venkatareddy MP, Wang SQ, Nishizono R, Suzuki T, et al. Growth-dependent podocyte failure causes glomerulosclerosis. J Am Soc Nephrol. 2012;23(8):1351–63. doi: 10.1681/ASN.2012030271 22773827

36. Fu Y, Zhu JY, Richman A, Zhang Y, Xie X, Das JR, et al. APOL1-G1 in Nephrocytes Induces Hypertrophy and Accelerates Cell Death. J Am Soc Nephrol. 2017;28(4):1106–16. doi: 10.1681/ASN.2016050550 27864430

37. Kriz W, Lemley KV. A potential role for mechanical forces in the detachment of podocytes and the progression of CKD. J Am Soc Nephrol. 2015;26(2):258–69. doi: 10.1681/ASN.2014030278 25060060

38. Hayek SS, Koh KH, Grams ME, Wei C, Ko YA, Li J, et al. A tripartite complex of suPAR, APOL1 risk variants and alphavbeta3 integrin on podocytes mediates chronic kidney disease. Nat Med. 2017;23(8):945–53. doi: 10.1038/nm.4362 28650456

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2019 Číslo 10