Genetics of kidney failure and the evolving story of APOL1
David J. Friedman, Martin R. Pollak
David J. Friedman, Martin R. Pollak
Published September 1, 2011
Citation Information: J Clin Invest. 2011;121(9):3367-3374. https://doi.org/10.1172/JCI46263.
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Science in Medicine

Genetics of kidney failure and the evolving story of APOL1

Abstract

Chronic kidney disease (CKD) results from a wide array of processes that impair the kidney’s ability to perform its major functions. As many as 20 million Americans suffer from CKD and nearly a half million from end-stage renal disease, but there are also examples of centenarians with adequate renal function. Family-based and genome-wide studies suggest that genetic differences substantially influence an individual’s lifetime risk for kidney disease. One emerging theme is that evolution of genes related to host defense against pathogens may limit kidney longevity. The identification of these genetic factors will be critical for expanding our understanding of renal development and function as well as for the design of novel therapeutics for kidney disease.

Authors

David J. Friedman, Martin R. Pollak

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Figure 2

ApoL1 circulates as part of the HDL3 complex, which includes hemoglobin and haptoglobin-related protein.

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ApoL1 circulates as part of the HDL3 complex, which includes hemoglobin ...
(A) In one current model, the ApoL1-containing complex is taken up by T. b. brucei via a receptor that binds hemoglobin and haptoglobin-related protein (Hb-Hpr). ApoL1 traffics to the trypanosomal lysosome, where the acidic pH causes a conformational change, leading to activation of anion channel function in the ApoL1 N terminus. Lysosomal swelling kills the trypanosome. Thus, ApoL1 confers innate immunity against this parasite. (B) Over time, T. b. brucei developed a virulence factor called SRA that can inactivate ApoL1 protein, although the cellular location of this interaction is unknown. These SRA-expressing trypanosomes evolved into T. b. rhodesiense, the etiologic agent that causes acute African sleeping sickness (57, 58). (C) The kidney disease–associated G1 and G2 variants encode forms of ApoL1 that evade SRA and remain active against T. b. rhodesiense. This, and/or other biological effects, may have conferred a selective advantage to G1 and G2 heterozygotes, causing a selective sweep. Figure adapted with permission from Current Opinion in Immunology (67).