Multiple studies have linked podocyte gene variants to diverse sporadic nephropathies, including HIV-1–associated nephropathy (HIVAN). We previously used linkage analysis to identify a major HIVAN susceptibility locus in mouse, HIVAN1. We performed expression quantitative trait locus (eQTL) analysis of podocyte genes in HIV-1 transgenic mice to gain further insight into genetic susceptibility to HIVAN. In 2 independent crosses, we found that transcript levels of the podocyte gene nephrosis 2 homolog (Nphs2), were heritable and controlled by an ancestral cis-eQTL that conferred a 3-fold variation in expression and produced reactive changes in other podocyte genes. In addition, Nphs2 expression was controlled by 2 trans-eQTLs that localized to the nephropathy susceptibility intervals HIVAN1 and HIVAN2. Transregulation of podocyte genes was observed in the absence of HIV-1 or glomerulosclerosis, indicating that nephropathy susceptibility alleles induce latent perturbations in the podocyte expression network. Presence of the HIV-1 transgene interfered with transregulation, demonstrating effects of gene-environment interactions on disease. These data demonstrate that transcript levels of Nphs2 and related podocyte-expressed genes are networked and suggest that the genetic lesions introduced by HIVAN susceptibility alleles perturb this regulatory pathway and transcriptional responses to HIV-1, increasing susceptibility to nephropathy.
Natalia Papeta, Ka-Tak Chan, Sindhuri Prakash, Jeremiah Martino, Krzysztof Kiryluk, David Ballard, Leslie A. Bruggeman, Rachelle Frankel, Zongyu Zheng, Paul E. Klotman, Hongyu Zhao, Vivette D. D’Agati, Richard P. Lifton, Ali G. Gharavi
Title and authors | Publication | Year |
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Background strain and the differential susceptibility of podocyte-specific deletion of Myh9 on murine models of experimental glomerulosclerosis and HIV nephropathy
DB Johnstone, O Ikizler, J Zhang, LB Holzman |
PloS one | 2013 |
Host APOL1 genotype is independently associated with proteinuria in HIV infection
MM Estrella, CM Wyatt, CL Pearce, M Li, MG Shlipak, BE Aouizerat, D Gustafson, MH Cohen, SJ Gange, WH Kao, RS Parekh |
Kidney International | 2013 |
Comparison of risk factors and outcomes in HIV immune complex kidney disease and HIV-associated nephropathy
MC Foy, MM Estrella, GM Lucas, F Tahir, DM Fine, RD Moore, MG Atta |
Clinical journal of the American Society of Nephrology : CJASN | 2013 |