Susceptibility loci for murine HIV-associated nephropathy encode trans-regulators of podocyte gene expression
Natalia Papeta, … , Richard P. Lifton, Ali G. Gharavi
Natalia Papeta, … , Richard P. Lifton, Ali G. Gharavi
Published April 20, 2009
Citation Information: J Clin Invest. 2009;119(5):1178-1188. https://doi.org/10.1172/JCI37131.
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Research Article

Susceptibility loci for murine HIV-associated nephropathy encode trans-regulators of podocyte gene expression

Abstract

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.

Authors

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

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Figure 4

Podocin (Nphs2) level is associated with mouse ancestral haplotype.

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Podocin (Nphs2) level is associated with mouse ancestral haplotype. ...
(A) Phylogeny of the Nphs2 sequence identified 3 major clades among 19 inbred strains. Numbers indicate the percentages of replicate trees in which the associated taxa clustered together in the bootstrap test (10,000 replicates). Scale indicates branch lengths and the evolutionary distances, measured as the number of base substitutions per site. (B) Nphs2 expression level in inbred mice was significantly associated with haplotype. Individual points indicate Nphs2 levels in mice of various strains, grouped by ancestral haplotype, with means shown for each group. Expression levels are shown as the ratio of the expression level of each sample relative to that of an internal reference sample (FVB). (C) Western blot analysis of podocin levels in the kidney of representative mouse strains confirmed quantitative PCR data. Positions of podocin and GAPDH (loading control) are indicated. M.m. mus, M.m. musculus; M.m. cast, M.m. castaneus; M.m. dom, M.m. domesticus.